A Phase I/Ib Trial of MK-3475 (Pembrolizumab) and Afatinib in EGFR-Mutant Non-small Cell Lung Cancer With Resistance to Erlotinib
Overview
- Phase
- Phase 1
- Intervention
- Afatinib Dimaleate
- Conditions
- Recurrent Non-Small Cell Lung Carcinoma
- Sponsor
- Jonathan Riess
- Enrollment
- 11
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD) Recommended Dose of Pembrolizumab in Combination With Lead in Pembrolizumab and Afatinib Dimaleate
- Status
- Completed
- Last Updated
- last year
Overview
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.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of MK-3475 (pembrolizumab) when given in combination with afatinib (afatinib dimaleate) in patients with advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) activating mutations who have progressive disease on erlotinib (erlotinib hydrochloride). SECONDARY OBJECTIVES: I. To assess in a preliminary manner the efficacy of this combination (response rate, disease control rate and progression free survival). OUTLINE: This is a dose de-escalation study of pembrolizumab. Patients assigned to 1 of 2 treatment arms. ARM I (DOSE DE-ESCALATION COHORT): Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. 6 patients were enrolled into Dose Level 0 at 40 mg QD of afatinib, no de-escalation was needed prior to expansion. ARM II (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. All 5 expansion patients were enrolled at the dose of 40 mg QD of afatinib. In both Arms, courses repeat every 21 days (for up to 2 years for pembrolizumab) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.
Investigators
Jonathan Riess
Principal Investigator
University of California, Davis
Eligibility Criteria
Inclusion Criteria
- •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
- •Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy
- •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
Exclusion Criteria
- •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 evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary
Arms & Interventions
Arm I (afatinib dimaleate, pembrolizumab)
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.
Intervention: Afatinib Dimaleate
Arm I (afatinib dimaleate, pembrolizumab)
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.
Intervention: Pembrolizumab
Arm II (pembrolizumab, afatinib dimaleate)
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.
Intervention: Afatinib Dimaleate
Arm II (pembrolizumab, afatinib dimaleate)
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.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) Recommended Dose of Pembrolizumab in Combination With Lead in Pembrolizumab and Afatinib Dimaleate
Time Frame: Day 21
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.
Secondary Outcomes
- 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)