Phase I Study of Single Agent Pembrolizumab MK-3475 in Patients with Progressive Locally Advanced or Metastatic Carcinomas, Melanoma and Non-Small Cell Lung Carcinomas, (Keynote 001)
There are 5 parts to this clinical research study. MD Anderson will be taking part in Parts B, D, and F. This consent form will cover Parts B, D, and F. The goal of Part B is to further test the highest tolerable dose of MK-3475 (pembrolizumab) that was found in Part A when given to patients with melanoma. The safety of this drug will also be studied. The goal of Part D is to study 2 dose levels of pembrolizumab when given to patients with melanoma. The goal of Part F is to study 2 dose levels of pembrolizumab when given to patients with lung cancer. Pembrolizumab is a drug that includes a protein naturally created by living cells. It is designed to help the body's natural defense system react against tumors by blocking proteins that cancers cells create to "turn off" the body's immune (defense) system.
Disease Group: Lung
Treatment Agent: MK-3475
Treatment Location: Both at MDACC & and Other Sites
Primary Objectives: 1) To evaluate and characterize the tolerability and safety profile of single agent MK-3475 in adult patients with unresectable advanced carcinoma including non-small cell lung cancer (NSCLC or melanoma (MEL). 2) To evaluate anti-tumor activity of MK-3475 in MEL and NSCLC per RECIST 1.1 3) To evaluate the extent of tumor response that correlates with the degree of biomarker positivity in the tumors of ipilimumab naive patients treated with MK-3475 with the intent that the cut point for the PD-L1 assay willb e explored and refined with tumor samples from ipilimumab-naive MEL. 4) To evaluate anti-tumor activity per RECIST 1.1 of MK-3475 in unselected MEL refractory to ipilimumab patients and MEL patients refractory to ipilimumab with PD-L1 expressing tumors. 5) To evaluate anti-tumor activity per RECIST 1.1 of MK-3475 in patients with NSCLC with at least one prior systemic therapy whose tumors express a high level of PD-L1. Secondary Objectives: 1) To evaluate the RR of unselected patients with MEL refractory to ipilimumab and MEL naïve to ipilimumab, patients with MEL refractory to ipilimumab and MEL naïve to ipilimumab whose tumors express PD-L1, and patients with NSCLC with at least one prior systemic therapy whose tumors express a high level of PD-L1, per immune-related response criteria. 2) To characterize the PK profile of single agent MK-3475. 3) To evaluate target engagement and modulation in peripheral blood program cell death-1 (PD-1) receptor occupancy and modulation of receptor activity. 4) To investigate the relationship between candidate efficacy biomarkers and anti-tumor activity of MK-3475: To evaluate the correlation between PD-L1 expression levels and anti-tumor activity of MK-3475 in patients with melanoma, excluding ipi-refractory patients as stated in the primary objectives, and separately, non-small cell lung cancer. To investigate other biomarkers (e.g., tumor infiltrating lymphocytes, PD-L2, PD-1 ribonucleic acid (RNA) signature profiles) that may correlate with tumor responses. To evaluate differences in tumor tissue characteristics in biopsies taken during or post-treatment with MK-3475 versus baseline. 5) To evaluate response duration, progression-free-survival and overall survival of MEL patients who are treated with MK-3475. 6) To evaluate response duration, progression-free survival and overall survival of NSCLC patients who are treated with MK-3475. Tertiary Objectives: To examine concordance between archival tumor tissues, formalin-fixed, paraffin embedded tissue (FFPET) and newly obtained frozen tumor tissue with respect to PD-L1 expression and other candidate efficacy biomarkers.
IRB Review and Approval Date: 03/06/2012
Recruitment Status: Closed
Projected Accrual: 1137
1) In Part B of the study, patients must have a histological or
cytological diagnosis of MEL with progressive locally advanced or
metastatic disease that is not amenable to definitive local therapy with
curative intent. Ipilimumab-naïve Patients: Patients naive to ipilimumab
may not have received more than 2 prior systemic treatment regimens for
treatment of MEL. Ipilimumab-treated Patients: After the first 13
patients are enrolled, patients who have had ipilimumab may be enrolled,
provided the following requirements are met: Full resolution of
ipilimumab related adverse effects (including immunerelated adverse
effects) and no treatment for these adverse events (AEs) for at least 4
weeks prior to the time of enrollment. Minimum of 12 weeks from the
first dose of ipilimumab and >6 weeks from the last dose.
2) #1 Contd. No history of severe immune related adverse effects from ipilimumab (CTCAE Grade 4; CTCAE Grade 3 requiring treatment >4 weeks). Unequivocal PD within 6 months of the first dose of ipilimumab.
3) #1 Contd.Ipilimumab-refractory Patients: With Amendment 05, 06 and 07 patients who have had ipilimumab may be enrolled, provided the following requirements are met (these patients are considered ipilimumab-refractory): Received at least two doses of ipilimumab (minimum dose of 3 mg/kg). Progressive disease after ipilimumab will be defined according to irRC. The initial evidence of PD is to be confirmed by a second assessment, no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression (this evaluation is based on investigator assessment; SPONSOR will collect imaging scans for retrospective analysis). Once PD is confirmed, initial date of PD documentation will be considered as the date of disease progression.
4) #1 Contd: Documented disease progression within 24 weeks of the last dose of ipilimumab. Patients who were re-treated with ipilimumab and patients who were on maintenance ipilimumab will be allowed to enter the trial as long as there is documented PD within 24 weeks of the last treatment date (with ipilimumab). Resolution of ipilimumab related AEs (including irAEs) back to Grade 0-1 and <10 mg/day prednisone or equivalent dose for irAEs for at least two weeks prior to first dose of study drug.
5) #1 Contd: No history of severe irAEs from ipilimumab CTCAE Grade 4 requiring steroid treatment. No history of CTCAE Grade 3 irAEs from ipilimumab requiring steroid treatment (>10 mg/day prednisone or equivalent dose) >12 weeks. Minimum of four weeks (wash out period) from the last dose of ipilimumab. Patients with BRAF V600mutant melanoma must have had a prior treatment regimen that includes vemurafenib, dabrafenib, or other approved BRAF and/or MEK inhibitors.
6) #1 contd. In Part D of the study, patients must have a histological or cytological diagnosis of MEL with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent. Patients must be naive to ipilimumab and may not have received more than 2 prior systemic treatment regimens for treatment of MEL.
7) #1 contd. In Part F of the study, patients must have a histologically-confirmed or cytologicallyconfirmed diagnosis of non-small cell lung cancer, Patients have tumor(s) amenable to biopsy. Under amendment 07, patients in F must have a known EGFR mutation and ALK translocation status. o Patients in F-1 should be EGFR wild type and without ALK translocation. o Patients in F-2 may have an EGFR mutation or ALK translocation and participate in this study if they have documented progression of their NSCLC on the appropriate tyrosine kinase inhibitor (only erlotinib or gefitinib, or crizotinib, respectively) and have documented progression of their NSCLC on subsequent platinum doublet chemotherapy. Randomized patients in F-1 and patients in F-2 must have tumors that express PD-L1 as determined by a central vendor. The exception is the 20 patients to be enrolled in F-2 whose tumors do not express PD-L1.
8) #1 Contd: Patients in F-1 must be naive to systemic treatment for NSCLC (adjuvant therapy may not have been administered within 1 year of the relapse). Under amendment 06, patients in F-2 must have experienced progression of locally advanced or metastatic NSCLC after at least two prior systemic antineoplastic regimens (adjuvant therapy will count as a regimen if administered within 1 year before the relapse). Under amendment 07, patients in F-2 have experienced progression of locally advanced or metastatic NSCLC after at least one prior systemic antineoplastic regimen, at least one of which must have been a platinum-containing doublet (adjuvant therapy will count as a regimen if administered within 1 year before the relapse).
9) #1 Contd: Investigator-determined radiographic progression of NSCLC by RECIST 1.1 on the most recent prior therapy (and on a tyrosine kinase inhibitor if the patient has an EGFR mutation or ALK translocation) must be determined. The site’s study team must have reviewed pre-trial images that are of diagnostic quality from at least 2 dates to confirm that radiographic progression has occurred per RECIST 1.1 following initiation of the prior therapy. Note, the imaging obtained during screening may be one of the dates reviewed. These pre-MK-3475 images should be submitted to the central imaging vendor for a possible retrospective analysis of this eligibility criterion. The central vendor will not be confirming eligibility prior to randomization. Those patients who have received prior thoracic radiation with a dose > 30 Gy must wait at least 26 weeks before the first dose of MK-3475. Patient has an estimated life expectancy of at least 12 weeks.
10) #2: Measurable disease: In Part A of the study, patients may have non-measurable disease. In Part B, C, D, and F of the study, patients must have measurable disease as defined per irRC (Appendix 6.5): i. Tumor mass: Must be accurately measurable in 2 perpendicular diameters, with both its longest diameter and its longest perpendicular must be greater than or equal to 10 mm or 2 times the axial slice thickness. Clinical lesions will only be considered measurable when they are superficial, such as skin or palpable lymph node. For MEL patients who are being screened for enrollment in Part B, after approval of Amendment 07, clinical lesions alone will not be considered as sufficient for enrollment; there must be measurable disease evident on CT imaging. ii. Malignant lymph nodes: Must be measurable in 2 perpendicular diameters, with both its longest diameter and its longest perpendicular, must be greater than or equal to 15 mm or 2 times the axial slice thickness.
11) #3: Patient is male or female and >/= 18 years of age on day of signing informed consent.
12) #4. Patient must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
13) #5. Patient must have adequate organ function as indicated by the following laboratory values: Hematological: Absolute neutrophil count (ANC) >/=1,500 /mcL; Platelets >/=100,000 mcL; Hemoglobin >/=9 g/dL or >/=5.6 mmol/L. Renal: Serum creatinine </=1.5 X upper limit of normal (ULN). Hepatic: Serum total bilirubin </= 1.5 X ULN OR Direct bilirubin </= ULN for patients with total bilirubin levels > 1.5 ULN. AST (SGOT) and ALT (SGPT) </= 2.5 X ULN OR </= 5 X ULN for patients with liver metastases. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) </=1.5 X ULN. Activated Partial Thromboplastin Time (aPTT) </=1.5 X ULN
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
1) Patient who has had chemotherapy, radioactive, or biological cancer
therapy within 4 weeks prior to the first dose of study therapy, or who
has not recovered to CTCAE grade 1 or better from the adverse events due
to cancer therapeutics administered more than 4 weeks earlier. Patient
who has had erlotinib, gefitinib, afatinib, or crizotinib within 1 week
prior to the first dose of study therapy, or who has not recovered to
CTCAE Grade 1 or better from the adverse events due to any of these
drugs administered more than 1 week earlier. o Patient who has had
ipilimumab therapy may be enrolled in Part B or Part C of the study
(after 13 ipilimumab naïve patients are enrolled in Part B) if the
requirements specified in Inclusion Criterion 1) are met.
2) Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of administration of MK-3475.
3) Patient is expected to require any other form of antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC).
4) Patient has a medical condition that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication. However, patients using physiologic replacement doses of hydrocortisone, or its equivalent, will be considered eligible for the study: up to 20 mg hydrocortisone (or 5 mg of predinosone) in the morning and 10 mg hydrocortisone (or 2.5 mg of predinosone) in the evening.
5) Patient has risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess, abdominal carcinomatosis).
6) Patient has a known history of a hematologic malignancy, malignant primary brain tumor or malignant sarcoma, or of another malignant primary solid tumor, unless the patient has undergone potentially curative therapy with no evidence of that disease for 5 years. o Note: The time requirement for no evidence of disease for 5 years does not apply to the tumor for which a patient is enrolled in the study. The time requirement also does not apply to patients who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
7) Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and are off steroids for at least 7 days from first dose of MK-3475.
8) Patient previously had a severe hypersensitivity reaction to treatment with another mAb.
9) Patient has a history of pneumonitis or interstitial lung disease
10) Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism that is stable on hormone replacement will not be excluded from the study.
11) Patient had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms (with exception of ipilimumab in study Part B and Part C).
12) Patient has an active infection requiring therapy.
13) Patient is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) active, Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected); patients with negative Hepatitis C antibody testing may not need RNA testing.
14) Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
15) Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16) Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
17) Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
18) Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.