Details

Details

Title A Phase 1b study of Crizotinib in combination with Pembrolizumab (MK-3475) in patients with untreated advanced ALK-translocated non-small cell lung cancer

IRB PFIZ1515

CC 15-1041

Hospital Main Campus

Phase Phase 1

Disease Lung - NSCLC (Non-small cell lung cancer)

Drug Crizotinib (Xalkori), Pembrolizumab

Description

Description

Primary Objective
  • To assess safety and tolerability of crizotinib in combination with pembrolizumab in the first-line treatment of patients with ALK-positive advanced non-squamous NSCLC in order to identify the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
Secondary Objectives
  • To evaluate the overall safety profile of crizotinib in combination with pembrolizumab;
  • To document the anti-tumor activity of crizotinib in combination with pembrolizumab in previously untreated ALK-positive advanced NSCLC patients;
  • To characterize the pharmacokinetics (PK) of crizotinib and pembrolizumab and to assess the effect of pembrolizumab on the PK of crizotinib;
  • To evaluate tumor PD-L1 expression, as assessed by PD-L1 immunohistochemistry, as a predictor of anti-tumor activity.
Exploratory Objectives
  • To characterize the development of anti-drug antibodies (ADAs) against pembrolizumab (immunogenicity evaluations);
  • To explore the predictive and, as appropriate, pharmacodynamic characteristics of additional tumor and peripheral blood biomarkers that may be relevant to the mechanism of action of, or the development of resistance to, crizotinib in combination with pembrolizumab;
  • To evaluate the impact of combination therapy of crizotinib and pembrolizumab on patient-reported lung cancer symptoms (such as dyspnea, cough and pain) and global Quality of Life (QOL) per the validated cancer specific EORTC QLQ-C30, and its lung cancer module, QLQ-LC-13, and visual symptoms per the Visual Symptom Assessment Questionnaire (VSAQ-ALK).
Inclusion Criteria

Inclusion Criteria

  1. Histologically or cytologically proven diagnosis of locally advanced, recurrent, or metastatic non-squamous NSCLC that is not suitable for local treatment with curative intent.
  2. ALK-positive NSCLC as determined by a test that is approved or validated for use as a companion diagnostic test in accordance with applicable local regulatory and practice guidelines.
  3. Able to provide formalin-fixed, paraffin-embedded (FFPE) tumor tissue (see Section 6.1.1).
  4. No prior systemic therapy for metastatic disease.
    • Any prior adjuvant chemotherapy for Stage I to III disease or combined modality chemoradiotherapy for locally advanced disease must have been completed >12 months prior to study enrollment.
  5. Tumors must have measurable disease as per RECIST (version 1.1); see Appendix 6.
  6. Age ≥18 years (or ≥20 years for Japan).
  7. ECOG PS must be:
    • 0 or 1 for the Dose Finding Phase.
    • 0, 1, or 2 for the Dose Expansion Phase.
  8. Adequate Bone Marrow Function, including:
    • Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
    • Platelets ≥100,000/mm3 or ≥100 x 109/L;
    • Hemoglobin ≥8 g/dL.
  9. Adequate Renal Function, including:
    • Serum creatinine <2x upper limit of normal (ULN).
  10. Adequate Liver Function, including:
    • Total serum bilirubin ≤1.5 x ULN;
    • AST and ALT ≤2.5 x ULN (≤5.0 x ULN if there is liver involvement secondary to tumor);
    • Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in case of bone metastasis).
  11. Serum or urine pregnancy test (for females of childbearing potential) negative at screening.
    • Male patients able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use 2 highly effective method(s) of contraception throughout the study and for 90 days after the last of crizotinib or 120 days after the last dose of pembrolizumab, whichever is later (see Section 4.3.1).
  12. Evidence of a personally signed and dated informed consent document indicating that the patient or legally acceptable representative has been informed of all pertinent aspects of the study.
  13. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other procedures.
Exclusion Criteria

Exclusion Criteria

  1. Prior exposure to ALK receptor tyrosine kinase inhibitors, anti-PD-1, anti-PD-L1, anti-PD-L2, Anti-CD137, or anti-CTLA-4 monoclonal antibodies (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  2. Current treatment on another clinical trial.
  3. Major surgery, adjuvant chemotherapy, radiotherapy, any investigational agents, or other anticancer therapy within 2 weeks prior to study enrollment or has not yet recovered (ie, Grade ≤1 or at baseline) from related acute adverse events more than 4 weeks earlier.
  4. History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or any grade of interstitial lung disease, including a history of any of the following conditions: pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis, but not history of prior radiation pneumonitis.
  5. Active autoimmune disease that has required systemic treatment in the past 3 months (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or corticosteroids at physiologic doses for eg. thyroid, pancreatic or adrenal insufficiency is acceptable.
  6. Known carcinomatous meningitis or leptomeningeal disease. Patients with brain metastases are only eligible if treated and neurologically stable with no ongoing requirement for corticosteroids, eg, dexamethasone, for at least 2 weeks and are not taking contraindicated medications.
  7. History of malignancy within the past 3 years (with the exceptions of non-squamous NSCLC, in situ cervical cancer, colon polyps, prostate carcinoma in situ or status postresection or radiotherapy, ductal carcinoma in situ of the breast, papillary thyroid cancer (resected and treated with curative intent), or resected/treated squamous cell or basal cell carcinoma of the skin).
  8. Active infection requiring systemic therapy.
  9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
  10. Known 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.
  11. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected).
  12. Administration of a live vaccine within 30 days prior to the first dose of trial treatment.
  13. Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, congestive heart failure, coronary/peripheral artery bypass graft, or cerebrovascular accident including transient ischemic attack. Appropriate treatment with anticoagulants is permitted.
  14. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, or machine-read ECG with QTc interval >470 msec.
  15. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap-band. Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed.
    • For Japan only: patients who have following complications or symptoms:
      • Serious wound such as chronic wound, or Grade ≥3 gastrointestinal ulcer.
      • Serious gastrointestinal symptoms such as Grade ≥3 diarrhea.
  16. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
  17. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of the study.
  18. Pregnant female patients; breastfeeding female patients; male patients with partners currently pregnant male patients able to father children and female patients of childbearing potential who are unwilling or unable to use 2 highly effective method(s) of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of crizotinib or 120 days after the last dose of pembrolizumab, or longer based upon the compound's half-life characteristics.
  19. Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconzole, and grapefruit or grapefruit juice. The topical use of these medications (if applicable), such as 2% ketoconazole cream, may be allowed.
  20. Use of drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.
  21. Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to dihydroergotamine, ergotamine, pimozide, astemizole*, cisapride*, and terfenadine* (*withdrawn from U.S. market).