Pembrolizumab and Afatinib in Patients With Non-small Cell Lung Cancer With Resistance to Erlotinib

NCT02364609 | Completed Phase 1 Results DMC FDA Drug

• 6 other identifiers: 704874UCDCC#2501200.237P30CA09337351657NCI-2015-00126
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.

Conditions

Recurrent Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) Recommended Dose of Pembrolizumab in Combination With Lead in Pembrolizumab and Afatinib Dimaleate

  MTD is defined as the dose were less than two patients experienced a dose limiting toxicity. Dose limiting toxicities are defined in the protocol and graded per CTCAE 4.0.

  Day 21

Secondary Outcomes (2)

• Overall Response Rate Per RECIST 1.1

  Up to 3 years

• Progression Free Survival

  Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

Study Arms (2)

Arm I (afatinib dimaleate, pembrolizumab)

EXPERIMENTAL

DOSE DE-ESCALATION COHORT: Patients receive afatinib dimaleate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days (for up to 2 years for pembrolizumab) in the absence of disease progression or unacceptable toxicity. 6 patients were enrolled into Dose Level 0 at 40 mg QD of afatinib, no de-escalation was needed prior to expansion.

Drug: Afatinib Dimaleate; Biological: Pembrolizumab

Arm II (pembrolizumab, afatinib dimaleate)

EXPERIMENTAL

EXPANSION COHORT: Patients receive pembrolizumab IV over 30 minutes on day 1 for 2 courses. Beginning course 3, patients receive afatinib dimaleate PO and pembrolizumab IV as in Arm I. Courses repeat every 21 days (up to 2 years for pembrolizumab) in the absence of disease progression or unacceptable toxicity. All five expansion patients were enrolled at the dose of 40 mg QD of Afatinib.

Drug: Afatinib Dimaleate; Biological: Pembrolizumab

Interventions

Afatinib Dimaleate DRUG

Given PO

Also known as: BIBW 2992MA2, BIBW2992 MA2, Gilotrif

Arm I (afatinib dimaleate, pembrolizumab); Arm II (pembrolizumab, afatinib dimaleate)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Arm I (afatinib dimaleate, pembrolizumab); Arm II (pembrolizumab, afatinib dimaleate)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator
• Be willing and able to provide written informed consent for the trial
• Have a life expectancy of at least 3 months
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale
• There is no limit to the number of prior treatments for this phase I trial
• Absolute neutrophil count (ANC) \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L
• Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) =\< 1.5 x upper limit of normal (ULN) OR \>= 60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN
• Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =\< 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN OR \< 5 x ULN for subjects with liver metastases
• International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

You may not qualify if:

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not \< 1 week prior to study day 1 and not administered on day of MK-3475 infusion
• Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
• Note: subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study
• Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study
• Has an active infection requiring intravenous systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)

Sponsors & Collaborators

• Jonathan Riess: lead
• National Cancer Institute (NCI): collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Afatinib; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

No limitations

Results Point of Contact

• Title: Leslie Garcia, Data Research Supervisor
• Organization: UC Davis Comprehensive Cancer Center

lesgarcia@ucdavis.edu

916-734-0156

Study Officials

• Jonathan Riess

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 10, 2015
• First Posted: February 18, 2015
• Study Start: September 30, 2015
• Primary Completion: April 26, 2018
• Study Completion: May 1, 2020
• Last Updated: October 16, 2024
• Results First Posted: October 16, 2024

Record last verified: 2024-10

Locations

US (1)