NCCN Request for Proposals (RFP): Preclinical, Phase I/II Clinical Trials and Correlative Studies of Afatinib in Combination with Other Drugs for Selected Cancers

NCCN Afatinib Combination RFP: 22JAN16

NCCN Request for Proposals (RFP): Preclinical, Phase I/II Clinical Trials and Correlative Studies of Afatinib in Combination with Other Drugs for Selected Cancers

1.0 Purpose

Boehringer Ingelheim Pharmaceuticals, Inc. (hereafter, “Grantor”) has agreed to provide National Comprehensive Cancer Network (NCCN) a 2 Million Dollar research grant to support NCCN Member Institution faculty for the performance of preclinical, clinical, and correlative studies of afatinib containing combinations in the treatment of lung and head and neck cancers. NCCN will serve as the funding organization for these grants that are available only to NCCN investigators. The following details the objectives, process and requirements of this RFP, which shall be subject to the terms and conditions of the Research Agreement.

The motivation behind this RFP is to facilitate the development of combination therapies using afatinib. Towards this goal, several specific additional therapies may be available from collaborating pharmaceutical companies, and are detailed below, though investigations addressing any combination regimens will be considered.

2.0 Background

NCCN has received a grant from the Grantor for the design and performance of preclinical and clinical studies using afatinib either alone or in combination with other agents to treat lung and head and neck cancers.

The aim of this RFP is to increase the body of clinical, preclinical and basic science knowledge concerning mechanisms of action (MOA), resistance and toxicity and specific patient populations which will aid in design and understanding of future clinical studies. Collaboration between NCCN Member Institutions is strongly encouraged in order to foster the interactive sharing of knowledge and expertise and to utilize the combined clinical and scientific strengths of members.

Overview
Primary Targeted Therapy: Afatinib

Afatinib is a Pan-HER targeting agent that has been approved for EGFR mutated lung cancer and has been studied in other diseases including squamous lung cancer, squamous head and neck, and HER2 mutant lung cancer. It targets EGFR, ERBB2 and ERBB4. Afatinib demonstrates a lack of cross-reactivity with other molecules and its binding is irreversible.

Although a number of studies have been conducted with this agent, two studies are highlighted here.

LUX-Lung 3 and LUX-Lung 6 were pivotal trials for afatinib in adenocarcinoma. These trials were conducted in patients with tumors harboring activating EGFR mutations.

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Patients were stratified by mutational status (Del19/L858R/other). Del19 and L858R mutations comprised approximately 90 percent of patients in each study (Del19: 50%, L858R: 40%). The primary endpoint of both these studies was progression-free survival (PFS). In LUX-Lung 3 afatinib monotherapy was compared to the platinum combination of cisplatin and pemetrexed. The median PFS was 13.6 months versus 6.9 months, in favor of afatinib. In LUX-Lung 6, afatinib monotherapy was compared to another commonly used platinum doublet, cisplatin and gemcitabine where the median PFS was 11.0 months versus 5.6 months again in favor of afatinib.

When broken down by mutation in LUX-Lung 3 and LUX-Lung 6 trials, patients with Del19 mutation demonstrated longer PFS with afatinib versus chemotherapy. In the afatinib arms of both studies, better PFS was demonstrated in the Del19 patients versus the L858R patients (13.7 months vs 10.8 months in Lux lung 3; and 13.7 months vs 9.6 months in Lux Lung 6 possibly suggesting differences between chemotherapy activity). The objective response rate (ORR) in LUX-Lung 3 for afatinib was 56% and for cisplatin plus pemetrexed was 23% (independent review). Subsequent therapies were balanced between the arms in both studies.

An analysis of OS by mutational status showed significant differences between Del19 and other mutations. Specifically, patients with Del19 demonstrated a striking improvement in overall survival when treated with afatinib (33.3 months for afatinib versus 21.1 months in Lux Lung 3, and 31.4 months versus 18.4 months in Lux Lung 6). There were no significant findings regarding OS in L858R patients (27.6 months versus 40.3 months in Lux Lung 3 and 19.6 months versus 24.3 months in Lux Lung 6). OS benefit in patients with Del19 was demonstrated in independent analysis of both LUX- Lung 3 and LUX-Lung 6.

Afatinib’s safety profile includes toxicities typically related to EGFR inhibition. It should be noted that 57% of patients in the trials were dose reduced from 40mg to 30mg and 19% of patients were additionally reduced from 30mg to 20mg. Approximately 40% of patients start on 40mg and stay on this dose for over a year. Dose reduction is effective in ameliorating side effects and does not affect PFS or OS. In LUX-Lung 3, Japanese patients were slightly more likely to be dose reduced than the rest of the patients in the trial (70-80% versus 60-70%, respectively), but their time on study was almost 100 days longer than the other patients.

LUX-Lung 8 compared afatinib to erlotinib in second line treatment of squamous cell carcinoma. Approximately 25% of patients were Asian. The primary endpoint was PFS based on independent review and it was statistically significantly better in favor of afatinib. The difference in the median PFS between the two arms was 0.7 months, (2.6 months vs 1.9 months) representing an 18% risk reduction in PFS with afatinib. OS analysis was also in favor of afatinib in this study with a median OS improvement of 1.1 months (7.9 months versus 6.8 months) representing a 19% risk reduction favoring afatinib. Differences in the safety profiles of afatinib and erlotinib were seen with greater incidence of diarrhea, rash/acne, and stomatitis with afatinib, but overall the adverse event (AE) profile was similar. Dose reductions were higher on the afatinib arm, but dose discontinuations were comparable between the two arms.

Thus, afatinib is an active agent in treatment of patients with EGFR mutations, particularly in Del19 position, and is an active agent in squamous cell lung cancer. Given

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the availability of other agents with potential ability to augment clinical efficacy of this agent, the current RFP is generated.

Potential Candidate Combination Agents:

Nivolumab

The programmed death-1 (PD-1) receptor is expressed on activated T cells. Once engaged by tumor-expressed ligands PD-L1 and PD-L2, it can downregulate T-cell activation and promote tumor immune escape.

Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, disrupts PD- 1-mediated signaling and restores antitumor immunity. Phase I studies of this agent in patients with multiple tumor types indicated significant clinical benefit in previously treated patients with NSCLC regardless of histology. Nivolumab received FDA approval in the United States for treatment of patients with metastatic squamous and non- squamous NSCLC and progression on or after a platinum-based chemotherapy. Patients with EGFR/ALK genomic aberration should have disease progression on FDA approved therapy prior to receiving Nivolumab. Checkmate 057 studied patients with non-squamous advanced NSCLC who had progressed following treatment with one platinum doublet chemotherapy. This trial compared nivolumab to docetaxel with a primary endpoint of overall survival. The one-year survival rates were 51% for nivolumab and 39% for docetaxel; the median OS was 12.2 months for nivolumab and 9.4 months for docetaxel. The rate of grade 3 and 4 treatment related AEs for nivolumab was low in this study and mostly immune-related in nature.

Checkmate-017 study was a randomized phase III study in patients with squamous cell carcinoma of the lung who had evidence of disease progression on or after platinum doublet chemotherapy. Patients were randomized to docetaxel vs nivolumab. The study showed that median OS was 9.2 months in the nivolumab group vs 6.0 months in the standard chemotherapy group translating in a 41% lowering of the risk of death in the nivolumab treated arm. The median PFS was also superior in the nivolumab arm of the study (median PFS 3.5 vs 2.8). As a result of this study, nivolumab was approved in March 2015 by the FDA for second-line treatment of this population.

In a subanalysis, predetermined patient populations were examined to determine if smoking and EGFR status affects nivolumab’s efficacy. This analysis suggests that current or former smokers derive more benefit than patients who never smoked. Likewise, patients with no documented EGFR mutation appear to derive more benefit from nivolumab than docetaxel. In the sub group of patients with known EGFR mutation status, most had received a previous TKI; however, the clinical outcomes after TKI treatment were not known. In this study, the ORR for nivolumab was 19% vs. 12% for docetaxel in the intent to treat population. These responses were durable.

Checkmate 012 enrolled treatment naïve patients with advanced NSCLC. This multi-arm study included cohorts of patients treated with either nivolumab monotherapy, nivolumab plus a platinum based doublet chemotherapy, nivolumab plus erlotinib, nivolumab plus bevacizumab, and nivolumab plus ipilimumab.

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The nivolumab plus erlotinib arm enrolled patients who had evidence of disease progression while on erlotinib (n=20) and one patient with no prior TKI exposure. No additive toxicities were noted with this combination. Out of the 21 patients in this arm, five patients responded (one was erlotinib naïve that had a complete response (CR)), two patients’ tumors were found to be negative for the T790M mutation, and two were T790M positive. Out of these five patients, three are currently two years out on nivolumab alone and are still responding (OS rate at 2 year of 45%).

A number of other studies are ongoing with this agent, including front line studies. A potential interaction between the EGFR and PD-1 pathways is suggested by a number of pre-clinical studies and remains an area of potential interest.

Necitumumab

Necitumumab is a second-generation human IgG1 antibody against EGFR. Two separate Phase 3 studies of necitumumab in squamous and non-squamous NSCLC have been conducted to date.

The INSPIRE study (enrolled patients with Stage IV non-squamous NSCLC) compared necitumumab plus the platinum doublet chemotherapy of cisplatin and pemetrexed to the same chemotherapy as a control arm. The primary endpoint of OS was not met. The development of necitumumab in combination with platinum-based chemotherapy in non- squamous NSCLC is not further pursued (Paz-Ares et al, 2015).

The SQUIRE study was conducted in patients with advanced squamous NSCLC. This study compared front line treatment with necitumumab plus cisplatin and gemcitabine to the same platinum doublet. Patients in both groups received up to 6 cycles of gemcitabine and cisplatin. Patients in the experimental arm in the absence of progressive disease continued to receive necitumumab monotherapy until progressive disease. The primary endpoint of OS was met with a favorable benefit/risk profile. The addition of necitumumab resulted in a 16% reduction in the risk of death (HR=0.84; p=0.012) and the effect was seen across the majority of pre-specified subgroups. The hazard ratio (HR) for PFS was also consistent at 0.85 (p=0.02). Safety profile was consistent with that expected for an EGFR monoclonal antibody. EGFR IHC results are available from approximately 90% of patients. The EGFR H-score cut-point of 200 was pre-specified, but this was not predictive of necitumumab benefit in this study. Further exploratory analyses did not identify any other cutpoint to differentiate a subpopulation that would derive more benefit from the addition of necitumumab. . An exploratory analysis of EGFR gene copy number gain (FISH) showed a trend for a more favorable HR in the assessable subset of patient tumors (51%), but without a statistically significant treatment-by-marker interaction (Thatcher et al, 2015; Hirsch et al, 2015).

Necitumumab is not approved yet and is currently under review by regulatory authorities in the US and the EU for first-line squamous NSCLC. Other studies of necitumumab in combination with other agents are ongoing in patients with NSCLC.

Ramucirumab

Ramucirumab is an IgG1 monoclonal antibody that binds to VEGFR-2 preventing the binding of VEGF ligands and subsequent activation. Ramucirumab in combination with

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docetaxel was approved for the second line treatment of patients with NSCLC, regardless of histology. This approval came as a result of a positive REVEL study. This registration, randomized, placebo controlled, Phase 3 study has demonstrated that the addition of ramucirumab to docetaxel prolonged OS in patients with stage IV squamous and non-squamous NSCLC who have progressed after platinum-based therapy. Median OS was 10.5 months for patients who received ramucirumab plus docetaxel and 9.1 months for patients who received placebo plus docetaxel (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.68-0.86; p<0.0001). Similar gains were seen in median OS across both histologies (the gain in median OS in non-squamous subgroup was 1.4 months and in squamous subgroup was 1.3 months). Neutropenia, febrile neutropenia and hypertension occurred more frequently in the experimental arm and most toxicities were manageable.

JVCG was the second randomized Phase 2 registration study using a lower dose of docetaxel in order to meet the regulatory requirements in Japan. The study met the pre- specified study objective of a HR for PFS <1 in the primary population. Two patient cohorts were enrolled; a primary study population of patients with stage IV NSCLC who had disease progression during or after one prior first-line, platinum based therapy without prior EGFR TKI treatment and an experimental cohort of patients with EGFR mutation-positive NSCLC who had disease progression on or after prior platinum-based chemotherapy and whose prior therapy included an EGFR TKI. Patients were randomized to receive ramucirumab plus docetaxel or placebo and docetaxel. At the time of data cut-off, the primary cohort median PFS for the experimental arm was 5.22 months versus 4.21 months, for the control arm, with a HR of 0.83. The median OS at the time of primary PFS analysis was 15.15 months for the experimental arm versus 13.93 for the control arm, with a HR of 0.77. The combination of ramucirumab plus docetaxel was well-tolerated with a manageable safety profile. Main grade 3/4 toxicities were febrile neutropenia and proteinuria.

3.0 Scope and Aims

The areas of research emphasis identified for this RFP include:

 Phase I/II studies in the identified tumor types;
o Afatinib drug combination studies including biologics are acceptable if the

toxicity profile of the agent is appropriate and there is sufficient data in the literature regarding the single agent activity of the combining drug so that the contribution of each drug can be determined.

o Multi-institutional Phase II trials to expedite the evaluation of afatinib as a single agent or in combination with any of the other agents listed in specific low incidence tumor types are appropriate.

o Innovative proposals including combination therapy for treatment of patients with squamous cell histology, TKI resistant, EGFRT790M negative NSCLC or Her2 mutant NSCLC are highly valued. Proposals assessing single agent afatinib therapy in NSCLC or head and neck tumors can be proposed if the study and its correlative studies elucidate a rationale for future novel approaches with combinations.

o Innovative proposals for early stage disease management are also desirable (excluding adjuvant lung trials).

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o If the combination proposal includes combinations of nivolumab, necitumumab or ramucirumab the drugs will be supplied as part of the grant. For other combinations, the proposal needs to take into account the provision of the drug.

  •   Preclinical studies that will shed light on novel uses and combinations of afatinib in cancer.
  •   Non-clinical correlates are appropriate — PKs for combination chemotherapy studies, mechanism of action, mechanisms of resistance, etc. Examples include:

o Correlative work to identify predictive markers of response and/or primary and acquired resistance.

o Correlative work in patients with EGFRT790M negative, TKI resistant NSCLC tumors.

o Studies that could potentially highlight treatment approaches that allow novel combinations of afatinib.

  •   Preference may be given to proposals for specific patient subsets of high unmet need. As an example, TKI resistant-NSCLC that is EGFRT790M negative
  •   No studies will utilize doses outside the range for which safety data is available

    If you wish additional information regarding whether a concept is already planned or funded, please email ORProposals@nccn.org or call Doreen Walker at 215-690-0565.

    The overall aim is to develop innovative studies to help determine the role of afatinib in combination with other therapies. It is hoped proposals submitted in response to this RFP will be useful in guiding further development of afatinib either as a single agent or in novel combinations. Studies with correlative endpoints are encouraged.

    Collaboration between NCCN Member Institutions is strongly encouraged in order to foster the interactive sharing of knowledge and expertise, and to utilize the combined clinical strengths of members and particularly in the case of uncommon tumors. In addition, NCCN’s Affiliate Research Consortium is positioned to collaborate as community sites for studies (http://www.nccn.org/clinical_trials/affiliates.aspx).

    The NCCN Request for Proposals Development Team (RFPDT) has developed a Request for Proposals (RFP) with a formalized review procedure to select the proposals of highest scientific merit. The NCCN RFPDT has overseen the development of the RFP and an NCCN Scientific Review Committee (SRC) composed of some members of this group and other NCCN clinical leaders will perform the review of applications.

    Specific exclusions from this RFP include:

 Adjuvant lung cancer trials.
For any study that contains Ramucirumab or Necitumumab we would require a

safety component, or independent safety study, prior to allowing any additional

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patients or studies to be performed. The rationale is to ensure the safety of the subjects, as currently there is no data to support the clinical safety of the combination with Afatinib.

Research areas that are Exclusionary for Necitumumab specific combinations:

  •   Trial designs that include combinations of necitumumab with platinum-based chemotherapy in non-squamous NSCLC or 2L combinations with Pemetrexed (Alimta).
  •   Any study design including head to head comparisons of necitumumab with any other EGFR mAb.
  •   Studies exploring doses of Neci not covered by labels/IB.
  •   Duplicative study (approved IIT thru Lilly process, or studies reported on

    Clinicaltrials.gov).

  •   Head and Neck Studies.

    Research areas that are Exclusionary for Ramucirumab specific combinations

  •   Combinations with triplet combos: bevacizumab or aflibercept, or checkpoint inhibitors (so a triplet combo with other anti-angiogenics – Afatinib + Ram + X). Preclinical triplets could be explored.
  •   Any study design, including head to head comparisons of Ramucirumab and any other VEGF inhibitor (includes preclinical).
  •   Studies exploring non-registered or unexplored doses with Ramucirumab (10mg/kg q2W or 10mg/kg q3W doses only allowed); pending safety RELAY assessment.
  •   Studies that would be a direct compete with our current 1st line registration program in EGFR+ NSCLC (ie. large P2/P3. Phase 1 is acceptable).
  •   Studies in combination with Radiotherapy or in patients with uncontrolled brain mets (safety).
  •   Duplicative study (approved IIT thru Lilly process, or studies reported on Clinicaltrials.gov).
  •   Head and Neck Studies. Nivolumab:

4.0

 

Trials that explore activity in patients with symptomatic/untreated brain metastasis
Head to head trials with afatinib

Study Time Frames

All approved studies are expected to commence, which is defined as the first patient receiving the first dose of study drug(s), no later than nine (9) months of notice of study approval and meet primary objective within two (2) years of commencement. A manuscript must be submitted to NCCN for review no later than nine (9) months after study endpoint achieved. These studies will be funded as described in Section 9.0 and should be designed with subject number commensurate with study time frames and funding.

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Studies of rarer subsets of NSCLC or head and neck cancer or those that require a large numbers of patients for statistical power must be multi-institutional. Network-appropriate studies will be considered as long as submitting PI is from an NCCN Member Institution.

The following types of studies will be accepted for review: Preclinical studies that can be completed within a 2 year timeframe.

Phase I studies are expected to meet primary objective within 2 years of commencement.

Single-arm Phase II studies are expected to explore new approaches that can be tested in larger confirmatory studies if positive results are obtained. It is expected that these studies will meet its primary objective within 2 years of commencement. To meet this goal, single-arm Phase II trials may be multi-institutional. Data management and monitoring of studies should be coordinated by the applying institution. Additional funding for the applying institution may be requested to support the additional resources required for this activity, if the study involves multi-institutional participation.

Correlative laboratory studies are expected to be completed within the same time frame as the corresponding clinical trial.

Larger randomized Phase II studies already supported through other mechanisms (i.e. cooperative group) will be considered for support where the support requested will be for correlative laboratory studies that are unfunded and enhance the evaluation of the patient data.

Randomized Phase II multi-institutional studies with an estimated 2-year completion. Multi-institutional data management and monitoring of these studies should be coordinated by the applying institution. Additional funding for the applying institution may be requested to support the additional resources required for this activity.

All studies will require documentation of the feasibility of accruing the targeted study population and all studies may be multi-institutional.

5.0 Proposals

In order to respond to the RFP, investigators will submit a proposal in the format delineated below to NCCN, which will be evaluated by the NCCN SRC.

Proposals are required to be submitted electronically to the NCCN research portal at https://www.mednetstudy.com/sgs/nccn/ and include a letter of support from the governing groups of the institution verifying:

1) Office of Sponsored Research approval
2) Department Chair/Division approval
3) Institutional budgetary review and approval
4) The priority status of the research stating if there are competing trials. If

competing trials, please verify that this trial will have a higher priority. 5) Documentation to support feasibility with at least one of the following:

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 Letter from institution’s Feasibility Committee if applicable
 Documentation by previous studies and accrual (if available, publications and

abstracts)
6) Letter(s) of support from participating institutions including name of PI at participating

institution and their feasibility

Letters should be addressed to Robert W. Carlson, MD, CEO, National Comprehensive Cancer Network, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034.

Proposals will provide concise documentation of the research plan. The proposal is expected to contain sufficient information to allow the reviewers to fully assess the scientific rigor of the proposed study. A full research project plan may be submitted as an attachment. A robust review of the statistical plan will be conducted and a statistical co-investigator must be included.

Clinical trial proposals should contain detailed information regarding the following areas:

5.1 Clinical Trials

  1. Title/TumorType
  2. Investigators and institutional affiliations
  3. Hypothesis with primary and secondary objectives
  4. BackgroundInformation
  5. Researchdesign
  6. Study population

    i. Stage

ii. Major inclusions/exclusions

  1. Treatment plan
  2. Endpoints/Statistical analysis including sample size and number of participating sites
  3. Feasibility
    1. Estimated time of completion/monthly accrual
    2. Previous experience with trials that had similar tumor type,

      phase of study or prior therapy

    3. Collaborators’ experience, including affiliates
    4. Competing trials – List all active, approved or in-review studies

      at your institution for which the same patient population is

      eligible

    5. Projected Accrual Dates (Month/Year)

5.2 Correlative/Preclinical Studies

  1. Hypothesis (include relevant background studies)
  2. Preliminarydata
  3. Study design (include methods for obtaining samples, administering

    forms, or performing radiologic studies)

  4. Studypopulation
  5. Methodology
  6. Analytic plan
  7. Feasibility

i. Accrual

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ii. Specimen acquisition

5.3 Budget using NCCN template

  1. Breakdown by major cost categories.
  2. Justification of major costs with enough detail to demonstrate how

    funding for major elements in the study will be allocated.

  3. For combined clinical and correlative studies, separate budgets for

    each component should be submitted.

  4. Salaries are capped at the current NIH salary cap
  5. No travel or publication costs will be covered

5.4 Ancillary Documentation

  1. An NCI format BioSketch of the Principal Investigator
  2. An appendix of supportive literature may be provided

6.0 Proposal Requirements

6.1 Submission

All proposals must be submitted electronically using the directions below and are due by 5:00 PM (EST) on February 19, 2016. No exceptions will be granted.

  1. Access the website at https://www.mednetstudy.com/sgs/nccn/
  2. Register for a user account by selecting the ‘Registration for New

    Investigators Only’ link displayed on the sign on page

  3. Locate your Institution / Hospital from the pick list, apply all required

    (*) data into the data entry area and save

  4. Access your email account to obtain your User ID and Password
  5. Re-access the website and apply your User ID and Password (case

    sensitive)

  6. Complete the website training (available in word document or video)
  7. Submit your study

For technical issues with submission, please call the MedNet helpdesk at 866-258-2735.

Studies that have safety issues, are already well-funded concepts, or are not consistent with the strategy for investigation as written in this RFP will not be reviewed by the SRC.

For questions or issues, please call Doreen Walker at (215) 690-0565. NCCN will seek to provide information to potential investigators regarding ongoing or completed studies of afatinib in order to avoid the submission of a proposal that is already a well-studied concept.

6.2 Requirements

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6.2.1 Human Biological Specimens: All specimens must be obtained under informed consent and IRB approval appropriate for the study. Compliance with all federal regulations is required.

6.2.2 IRB:

6.2.2(a) Draft protocols will be reviewed by NCCN, Grantor and companies supplying drug through this grant prior to IRB review. A copy of the draft protocol must be submitted to NCCN within 4 weeks after the study approval letter. The protocol must be consistent with the approved proposal and all reviewer comments must be addressed.

6.2.2(b) All investigators will submit protocols for IRB review and document approval to NCCN prior to study activation and all collaborators will furnish evidence of IRB approval. It is expected that IRB review and approval be completed within 120 days following NCCN notification of funding for the project.

6.2.3 IACUC review and approval: All investigators conducting animal experiments will submit research project plans for IACUC review and document approval to NCCN prior to study activation. It is expected that IACUC review and approval be completed within 90 days following NCCN notification of funding for the project.

6.2.4 Serious Adverse Event Reporting: All serious adverse events will be reported to NCCN, Grantor and all companies supplying drug in addition to local regulatory authorities.

6.2.5 Institutional Monitoring: All studies will be internally monitored in accordance with appropriate committees (e.g. institutional Data Safety and Monitoring Plan in the case of human studies). A copy of the Data Monitoring Plan for the study must be submitted to NCCN prior to NCCN approval of study activation.

6.2.6 IND:
6.2.6(a) Investigators are required to hold INDs for studies but will

be allowed to cross-reference a filing to Grantor’s IND as well as companies supplying drug through this grant. Investigators are encouraged to apply to the FDA for IND exemption if studies meet all criteria according to 21 CFR 312.2(b). A copy of the FDA approval letter for IND exemption must be submitted to NCCN before study drug will be released.

6.2.6(b) If afatinib is studied in combination with an investigational agent from another pharmaceutical company, or an agent used outside of its indication, the investigator must provide documentation of that company’s commitment to provide drug for the investigation as well as the agreement of that company to allow presentation and publication of results and allow cross-filing or filing of a new IND. This documentation must be provided to NCCN along with the proposal.

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6.2.6(c) Proposals using an experimental diagnostic imaging agent that will require an IND must outline how regulatory issues will be handled in order to meet the required study time frame.

6.2.7 Progress Reports: Investigators will provide interim progress reports to NCCN detailing the progress of studies quarterly, and upon study completion. These reports will be used administratively for funding purposes. If study progress or accrual lags behind the expected rate, the SRC may be asked for suggestions to improve study progress, or alternatively, to terminate the study and any further funding.

6.2.8 Specimen Transmittal: If specimens are to be transported extramurally for collaborative laboratory studies, all institutional requirements for safety and confidentiality will be met.

6.2.9 Abstracts and Publications: Abstracts for presentation at scientific meetings and all publications of study results will be submitted to NCCN for review prior to any submission. Abstracts must be submitted at least 10 days prior to submission and manuscripts at least 30 days prior to submission. NCCN will provide the abstract/manuscript to Grantor and any company providing study drug through this grant for their review related to protection of company’s intellectual property and confidential information. The Grantor or study drug provider may delay publication and disclosure of the manuscript or abstract for up to an additional sixty (60) days so as to seek patent protection of intellectual property rights.

6.2.10 NCCN Multi-Institutional Studies: Collaborative studies between NCCN Member Institutions are encouraged. For these studies, the proposal feasibility section should provide information about data management, statistical analysis, and specimen handling issues. Additional funding may be provided for centralized data management and monitoring by the applying institution.

6.2.11 NCCN institutions and investigators will be responsible for conducting all studies in accordance with the applicable research plan, GCP Guidelines, and all applicable laws and regulations. NCCN institutions and investigators will be responsible for all data collection, statistical analysis and safety reporting.

6.2.12 Investigators must provide reasonable assurance that submitted studies will be able to reach completion within the time frames specified in Section 4.0.

6.2.13 Final protocols must be consistent with approved proposals. Funds will be rescinded if there are significant changes without prior NCCN approval. There will be no exceptions.

6.2.14 The Principal Investigator (PI) listed on the protocol must be the same PI listed on the proposal submission unless approved by NCCN.

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7.0 Drug Supply

Afatinib will be supplied for all approved and funded studies by Grantor. If the combination proposal includes combinations of nivolumab, necitumumab or ramucirumab, the drugs will be supplied as part of the grant. For other combinations, the proposal needs to take into account the provision of the drug.

8.0 Selection Criteria

Proposals will be judged based on the following criteria:

  1. Scientific value
  2. Research experience of the Principal Investigator
  3. Soundness of study design
  4. Feasibility including reasonable assurance of achieving intended and full

    Accrual

  5. Budgetary reasonableness
  6. Statistics

Any proposal that has safety issues or is an already studied concept may be rejected.

9.0 Funding

NCCN and its member institutions have an agreement to include a maximum of 25% indirect costs for trials funded by the NCCN. Direct funding will include all costs including investigators’ salaries. For example, $80,000 direct costs and $20,000 indirect costs for a total grant of $100,000. Any funds in excess of the limits stipulated in this section for direct funding will require detailed justification and review.

Phase I and Single-arm Phase II clinical trials will be funded at a cost of up to $300,000 (total costs including direct costs and 25% indirect costs) per trial. Per patient costs will not exceed $12,000 per patient. Multi-institutional data management and monitoring of these studies should be coordinated by the applying institution. Additional funding for the applying institution may be requested to support the additional resources required for this activity.

The Correlative Laboratory studies section of the clinical trial will be funded up to a total cost of $200,000, including up to 25% indirect costs.

Funding should not exceed $600,000. Clinical study maximum $300,000 + correlative study maximum $200,000 + multi-institutional funding maximum $100,000 = $600,000 MAXIMUM funding.

Preclinical studies will be funded up to a total cost of $200,000, including up to 25% indirect costs.

Preclinical Research Projects:
 50% of total award for such Study upon approval of funding

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NCCN Afatinib Combination RFP: 22JAN16

  •   35% of total award upon completion of research and receipt of final report
  •   15% of total award upon submission of a final summary report or manuscript for

    publication

    Phase I trials:

  •   25% of total award for such Study after IRB approval and implementation
  •   Funds will be awarded on a quarterly basis for eligible Study subjects enrolled in

    Study, based on the per Study subject rate up to a maximum of 90% of the

    funding

  •   10% of funds will be awarded after submission of a final summary report or

    manuscript for publication

    Phase II trials and Correlative studies:

  •   25% of total award for such Study after IRB approval and implementation
  •   35% of total award after 50% accrual
  •   30% of total award after 100% accrual
  •   10% of funds will be awarded after submission of a final summary report or

    manuscript for publication

    Phase I/II trials:

  •   25% of total award after IRB approval and implementation of the Phase I Study
  •   35% of total award after 50% accrual of Study subjects are enrolled in the Phase

    II Study

  •   30% of total award after 100% accrual of Study subjects to the Phase II Study
  •   10% of funds will be awarded after submission of manuscript for publication or a

    final summary report of the Study

    Larger Randomized Phase II trials already supported through other mechanisms (i.e. cooperative group) will be considered for support where the support requested will be for correlative laboratory studies that are unfunded and enhance the evaluation of the patient data. Correlative studies for larger randomized trials will be funded up to $200,000.

    The goal is to have rapid submission of a manuscript so as to have the data available to the wider scientific community.

    Studies that do not meet the time frame requirements as stipulated in Section 4.0 will have funds rescinded and will be required to return any and all unused funds previously disbursed.

10.0 Study Agreement

A study agreement will be signed between NCCN and each participating institution.

If an institution requires a separate contract with another pharmaceutical company for a study, that contract must be fully executed by the time of final contract execution with NCCN.

CONFIDENTIAL

Page 14 of 15

NCCN Afatinib Combination RFP: 22JAN16

All aforementioned points between NCCN and the participating institution must be strictly adhered to.

11.0 References

Hirsch FR, et al. EGFR IHC and FISH Correlative Analyses (SQUIRE trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-line Squamous NSCLC. World Conference on Lung Cancer; Denver, September, 2015.

Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, deCastro G Jr, de Souza Viana L, Keilholz U, del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomized phase 3 trial. Lancet Oncol. 2015 Apr; 16(5): 583-94. DOI: http://dx.doi.org/10.1016/S1470-2045(15)70124-5

Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA; INSPIRE investigators. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015 Mar;16(3):328-37.

Soria JC, Felip E, Cobo M, Lu S, Konstantinos S, Lee KH, Goker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomized controlled phase 3 trial. Lancet Oncol. 2015 Jul; 16(8), 897-907. DOI: http://dx.doi.org/10.1016/S1470-2045(15)00006-6.

Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74

CONFIDENTIAL

Page 15 of 15

Appendix 1
Clinical trials that have assessed afatinib-based combination regimens in oncology.

Regimen

Trial ID

Phase

Setting

n

MTD

Response, %

Adverse events, all/grade ≥3, %

Ref

Inhibitors of other intracellular signaling pathways

Afatinib plus sirolimus (mTOR inhibitor)

NCT00993499

I

EGFR mutation-positive NSCLC and/or disease progression following prior clinical benefit on gefitinib/erlotinib

39

Afatinib: 30 mg/day Sirolimus: 1 mg/day 28-day cycles

PR: 10 SD: 59

Diarrhea: 95/28 Mucosal inflammation: 62/15

Rash: 54/3 Asthenia:44/5

1

Inhibitors of other growth factor receptors

Afatinib plus nintedanib (VEGFR, PDGFR and

NCT00998296

I

Advanced solid tumors

28

Afatinib: 10 mg/day Nintedanib: 200 mg twice daily

PR: 4 SD: 32

Diarrhea: 79/NA Nausea : 71/NA Anorexia: 50/NA Vomiting: 43/NA

2

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16 Page 1 of 10

FGFR inhibitor)

28-day cycle

Fatigue: 43/NA

Afatinib plus bevacizumab (VEGF antibody) plus paclitaxel

NCT00809133

Ib

Advanced solid tumors

29

Not reported yet

Not reported yet

Not reported yet

3

Other ErbB inhibitors

Afatinib plus cetuximab (EGFR antibody)

NCT01090011

Ib

EGFR mutation-positive NSCLC and/or disease progression following clinical benefit on prior gefitinib/erlotinib

126

Afatinib: 40 mg/day Cetuximab: 500 mg/m2 every 2 weeks

PR: 29 SD: 41

Rash: 90/20 Diarrhea: 71/6 Nail effects: 57/0 Stomatitis: 56/1

4

Afatinib plus nimotuzumab (EGFR antibody)

NCT01861223

Ib/II

EGFR mutation-positive NSCLC and/or disease progression following clinical benefit on prior

37

Afatinib: 40 mg/day Nimotuzumab: 100 mg/week

OR: 38 SD: 43

Grade 3 AEs: 27

5

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

gefitinib/erlotinib

Afatinib plus trastuzumab (HER2 antibody)

NCT00950742

I

HER2-positive advanced breast cancer

18

Afatinib: 20 mg/day Trastuzumab: 4 mg/kg Week 1; 2 mg/kg week thereafter

PR: 11 SD: 28

Diarrhea: 94/50 Rash: 56/0 Fatigue: 56/0 Nausea: 50/0

6

Neoadjuvant afatinib plus trastuzumab

NCT01594177

II

Untreated HER2-positive breast cancer

65

Afatinib: 20 mg/day Trastuzumab: 6 mg/kg/3 weeks for 6 weeks, followed by afatinib, trastuzumab and paclitaxel (80 mg/m2/week) for 12 weeks followed

pCR: 70

Diarrhea: 71/5 Rash: 52/0 Mucositis: 31/0 Fatigue: 26/0

7

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

by epirubicin, cyclophosphamide and trastuzumab

Chemotherapy

Afatinib plus docetaxel

NCT02171741

I

Advanced solid tumors

31

Afatinib: 20 mg/day (Days 2‒ 21)
Docetaxel: 75 mg/m2 (Day 1) 21-day cycle

OR: 0 SD: 45

Diarrhea: 74/NR Neutropenia: 65/NR
Rash: 39/NR

Pulsatile afatinib plus docetaxel

NCT02171676

I

Advanced solid tumors

40

Afatinib: 90 mg/day (Days 2‒4) Docetaxel: 75 mg/m2 (Day 1) 21-day cycle

OR: 13 SD: 23

Alopecia: 50/0 Diarrhea: 50/5 Stomatitis: 50/0 Rash: 40/0

8

Afatinib plus paclitaxel

NCT00809133

I

Advanced solid tumors

16

Afatinib: 40 mg/day

PR: 31 SD: 13

Diarrhea: 94/0 Fatigue: 81/13

9

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

Paclitaxel: 80 mg/m2 (Days 1, 8, 15)
28-day cycle

Rash/acne: 81/6 Mucosal inflammation:69/6 Decreased appetite: 69/0

Afatinib plus paclitaxel

NCT01085136

III

NSCLC following chemotherapy, erlotinib/gefitinib and afatinib (≥12 weeks clinical benefit on each line of TKI therapy)

132

Afatinib: 40 mg/day
Weekly paclitaxel 80 mg/m2/week 28-day cycle

CR: 1 PR: 31 SD: 43

Diarrhea: 54/12 Alopecia: 33/1 Asthenia: 27/8 Decreased appetite: 22/2

10

Afatinib plus paclitaxel, cisplatin

NCT00716417

I

Advanced solid tumors

26

Afatinib 20 mg/day Paclitaxel 175 mg/m2 Day 1 Cisplatin 75 mg/m2 Day 1

21-day cycle

CR: 7 PR: 12 SD:35

Diarrhea: 89/23 Nausea: 85/19 Fatigue: 62/31 Anemia: 62/8

11

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

Afatinib plus paclitaxel plus carboplatin

NCT01732640

I/II

Induction therapy in patients with HPV- negative HNSSC

Ongoing

Ongoing

Ongoing

Afatinib plus paclitaxel, carboplatin, ribovarin

NCT01721525

I

Induction therapy in patients with HPV- associated OPSCC

Ongoing

Ongoing

Ongoing

Afatinib plus vinorelbine

NCT00906698

I

Advanced solid tumors known to overexpress EGFR and/or HER2

55

Afatinib: 40 mg/day Vinorelbine: 25 mg/m2/week iv or 60–80 mg/m2/week po

PR: 5 SD:45

Diarrhea: 52/NA Asthenia: 50/NA Nausea: 35/NA Decreased appetite: 33/NA

12

Afatinib plus vinorelbine

NCT01214616

I

Japanese patients with advanced solid tumors

17

Afatinib: 40 mg/day Vinorelbine: 25 mg/m2/week

PR: 11 SD: 17

Leukopenia: 100/59 Neutropenia: 100/71

13

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

Diarrhea: 94/0 Anemia: 71/12

Afatinib plus vinorelbine

NCT01125566

III

HER2-positive metastatic breast cancer patients after one prior trastuzumab treatment

339

Afatinib: 40 mg/day Vinorelbine: 25 mg/m2/week

Not reported

Diarrhea: 80/NA Neutropenia: 75/NA
Rash: 45/NA

14

Afatinib plus vinorelbine

NCT01441596

II

HER2-positive metastatic breast cancer patients with brain metastases

38

Afatinib: 40 mg/day Vinorelbine: 25 mg/m2/week

OR: 8 SD: 63

Diarrhea: 84/24 Rash: 54/5 Neutropenia:51/38 Mucosal inflammation: 32/8

15

Afatinib plus cisplatin, 5- fluorouracil

NCT00716417

I

Advanced solid tumors

21

Afatinib 30 mg/day 5-fluorouracil: 750 mg/m2 over Days 1–4

Cisplatin 75 or 100

CR: 5% SD: 24%

Nausea: 91/24 Diarrhea: 86/19 Fatigue: 76/29 Decreased appetite: 76/43

11

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

mg/m2 Day 1 21-day cycle

Afatinib plus pemetrexed

NCT01169675

I

Advanced solid tumors

23

Afatinib: 30 mg/day Pemetrexed: 500 mg/m2 Day 1 21-day cycle

CR: 4% SD: 26%

Diarrhea: 90/NA Stomatitis: 60/NA Rash: 55/NA Fatigue: 55/NA

16

Afatinib plus gemcitabine

NCT01251653

I

Relapsed or refractory solid tumors

19

Afatinib: 40 mg/day Gemcitabine: 1000 mg/m2 Days 1, 8 21-day cycle

Not reported

Diarrhea: 90/NA Rash: 63/NA

17

References

1. Moran T, Palmero R, Provencio M et al. A Phase Ib open label clinical trial of continuous once daily oral afatinib (A) plus sirolimus (s) in patients (pts) with EGFR mutation positive (EGFR M+) NSCLC and/or disease progression following prior erlotinib (E) or gefitinib (G). Ann Oncol. 25(Suppl. 4), iv437 (2014).

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

  1. GordonMS,SpringettGM,SuYBetal.AphaseIdose-escalationstudyofafatinibcombinedwithnintedanibinpatientswith advanced solid tumors. Future Oncology. 11(10), 1479-1491 (2015).
  2. Enting D, Ang JE, O’Hanlon-Brown C et al. A phase I study of daily afatinib, an irreversible ErbB family blocker, combined with weekly paclitaxel and 2-weekly bevacizumab in patients with advanced solid tumours. Presented at: 37th European Society of Medical Oncology Congress. Vienna, Austria, 28 September-2 October 2012 (Abstract 464P).
  3. Janjigian YY, Smit EF, Groen HJ et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 4(9), 1036-1045 (2014).
  4. Ahn MJ, Lee JY, Sun JM et al. A phase Ib/II study of afatinib in combination with nimotuzumab in non-small cell lung cancer patients with acquired resistance to gefitinib or erlotinib. Presented at: 51st Annual Meeting of the American Society of Clinical Oncology. Chicago, IL, USA, 29 May-2 June 2015. (Abstract 8086).
  5. Ring A, Wheatley D, Hatcher H et al. Phase I Study to Assess the Combination of Afatinib With Trastuzumab in Patients With Advanced or Metastatic HER2-Positive Breast Cancer. Clin Cancer Res. Epub ahead of print (2014).
  6. Hanusch C, Schneeweiss A, Loibl S et al. Dual Blockade with Afatinib and Trastuzumab as Neoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane-Anthracycline Containing Chemotherapy- DAFNE (GBG-70). Clin Cancer Res. 21(13), 2924-2931 (2015).
  7. Awada AH, Dumez H, Hendlisz A et al. Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors. Invest. New Drugs. 31(3), 734-741 (2013).
  8. Suder A, Ang JE, Kyle F et al. A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours. Eur J Cancer. (15), 10 (2015).
  9. Schuler MH, Yang CH, Park K et al. Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatanib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatanib–LUX-Lung 5 (LL5). Presented at: 50th Annual Meeting of the American Society of Clinical Oncology. Chicago, IL, USA, 30 May-3 June 2014. (Abstract).

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

  1. Vermorken JB, Rottey S, Ehrnrooth E et al. A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors. Ann Oncol. 24(5), 1392-1400 (2013).
  2. Hollebecque A, Bahleda A, Bergé Y et al. A phase I trial assessing the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumours. Presented at: 3rd Biennial European Cancer Congress. Amsterdam, The Netherlands, 27 September-1 October 2013. (Abstract 892).
  3. Mukai H, Masuda N, Ishiguro H et al. Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer. Cancer Chemother Pharmacol. 76(4), 739-750 (2015).
  4. Harbeck N, Huang C-S, Hurvitz SA et al. Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1. Presented at: 2014 San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9-13 December 2014. (Abstract P5-19-01).
  5. Cortes J, Dieras V, Ro J et al. Randomized Phase II trial of afatinib alone or with vinorelbine versus investigator’s choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib- based therapy: LUX-Breast 3. Presented at: 2014 San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9-13 December 2014. (Abstract P5-19-07).

16. Chu QS, Sangha R, Hotte SJ et al. A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors. Invest New Drugs. 32(6), 1226-1235 (2014).

17. Zanetta S, Bennouna J, Isambert N et al. Phase I safety and tolerability of once daily oral afatinib (A) (BIBW 2992) in combination with gemcitabine (G) in patients (pts) with advanced solid tumours. Presented at: 37th ESMO Congress. Vienna, Austria, 28 September-2 October 2012. (Abstract 478).

Appendix 1 NCCN Afatinib in Combination RFP: 22JAN16

Appendix 2 NCCN Afatinib Combination RFP: 22JAN16

Appendix 2
Open Afatinib Combination Studies

Study

Phase

Status

Location

NSCLC

Inhibitors of other intracellular signaling pathways

Dasatinib plus afatinib: EGFR mutation-positive NSCLC and disease progression following prior clinical benefit on gefitinib/erlotinib/afatinib or known T790M mutation

NCT01999985

I

Ongoing

US

Afatinib + Selumetinib (MEK Inhibitor) in Advanced KRAS mutation-positive CRC, NSCLC and pancreatic cancer

NCT02450656

I/II

Ongoing

Netherlands

Inhibitors of other growth factor receptors

Afatinib Plus Bevacizumab after Acquired Resistance to EGFR-TKI in EGFR- mutated NSCLC

II

Ongoing

Japan

Afatinib plus BI 836845 (IGF inhibitor) in patients with EGFR mutant NSCLC with progression following prior EGFR tyrosine kinase inhibitor and without T790M NCT02191891

Ib

Ongoing

Korea, Taiwan, Singapore

Other ErbB inhibitors

Phase Ib dose escalation study of afatinib in combination with cetuximab in patients with advanced solid tumours

Ib

Ongoing

France/Spain

Randomized Phase III

III

Ongoing

SWOG study in US

1

trial of Afatinib plus cetuximab vs afatinib alone in treatment naïve pts with adv, EGFR mutation positive NSCLC (1st-line) NCT02438722

Afatinib plus Cetuximab for EGFR-Mutant Advanced Lung Cancers (1st line)

III

Ongoing

France

Prospective, single arm study of afatinib plus Nimotuzumab in NSCLC patients who progressed with reversible EGFR TKI

Ib

Ongoing

Korea

Immunotherapy

Pembrolizumab + Afatinib in EGFR+ Non- Small Cell Lung Cancer With Acquired Resistance to Erlotinib: Bridge to First Line Therapy
NCT02364609

I

Ongoing

US

Chemotherapy and Others

Randomized open-label phase II trial comparing afatinib plus simvastatin and afatinib plus best supportive care in previously treated patients with advanced non-adenocarcinoma of lung

II

Ongoing

Korea

Sequential 2nd Line Chemotherapy with Pemetrexed Followed by Afatinib for Advanced NSCLC

II

Ongoing

Korea

Pemetrexed plus Intercalated Afatinib versus Pemetrexed Alone in Patients with EGFR Mutation Positive Advanced NSCLC after initial EGFR Tyrosine Kinase Inhibitor failure

II

Ongoing

Canada

Appendix 2 NCCN Afatinib Combination RFP: 22JAN16

2

Selected Afatinib single agent

NCI MATCH study: EGFR and HER2 arms – in non NSCLC tumors

Ongoing

US

Afatinib as neoadjuvant treatment for NSCLC

I

Ongoing

US

Colorectal cancer

Randomized phase II study of afacet vs cetuximab in patients with chemotherapy refractory wtKRAS metastatic CRC NCT01919879

II

Ongoing

France

Head and Neck Squamous cell carcinoma

Phase I Study of Afatinib with Postoperative Radiation Therapy for Intermediate and High Risk Squamous Cancer of the Head and Neck (SCCHN)

Ib

Ongoing

US

A Phase I/II study of Induction chemotherapy with Afatinib/ Carboplatin/Paclitaxel followed by standard chemoradiationin HPV negative locally advanced stage III/IVa/IVb HNSCC

I/II

Completed Phase I dose escalation. Study ended

US

Gastric Cancer

A Phase II study of Afatinib & Trastuzumab in Patients with Advanced HER2- postive Trastuzumab- Refractory Advanced Esophagogastric Cancer
NCT01522768

II

Ongoing

US

Breast

Afatinib plus trastuzumab (3-weekly) in HER2-positive

I

Ongoing

France

Appendix 2 NCCN Afatinib Combination RFP: 22JAN16

3

metastatic breast cancer NCT01649271

Appendix 2 NCCN Afatinib Combination RFP: 22JAN16

4

About the author: CU Cancer Center

Located on the Anschutz Medical Campus, the University of Colorado Cancer Center is Colorado’s only National Cancer Institute-designated comprehensive cancer center, a distinction recognizing its outstanding contributions to research, clinical trials, prevention and cancer control. CU Cancer Center is a member of the prestigious National Comprehensive Cancer Network®, an alliance of the nation’s leading cancer centers working to establish and deliver the gold standard in cancer clinical guidelines. CU Cancer Center is a consortium of more than 400 researchers and physicians at three state universities and six institutions, all working toward one goal: Translating science into life.

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