Details
Title A Phase I/II Study of MK-3475 (SCH900475) in Combination with Chemotherapy or Immunotherapy in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Carcinoma
IRB MRK 1513
CC 14-287
Hospital Main Campus
Stage Stage 3B, Stage 4
Phase Phase 1, Phase 2
Disease Lung, Lung - NSCLC (Non-small cell lung cancer)
Drug Pembrolizumab
Description
Primary Objectives
- To determine the recommended Phase II dose for MK-3475 in combination with chemotherapy or immunotherapy in subjects with unresectable or metastatic NSCLC.
- To evaluate anti-tumor activity based on RECIST 1.1 of MK-3475 in combination with chemotherapy or immunotherapy in NSCLC using PFS for cohort G1 and objective response rate for cohort H.
Secondary Objectives
- To evaluate the overall survival (OS) in subjects with unresectable or metastatic NSCLC treated with MK-3475 in combination with chemotherapy or immunotherapy.
- To characterize the pharmacokinetic (PK) profile of MK-3475 when given in combination with chemotherapy or ipilimumab or TKI (gefitinib or erlotinib.)
- To evaluate anti-tumor activity based on modified RECIST 1.1 of MK-3475 in combination with chemotherapy or immunotherapy or TKI (Part 1).
- To evaluate the correlation between PD-L1 expression levels and anti-tumor activity of MK-3475 in cohort G1.
Exploratory Objectives
- To evaluate PFS and OS following crossover to MK-3475 in subjects treated with chemotherapy alone until disease progression.
- To evaluate response duration per RECIST 1.1 by independent radiologists' review in subjects with unresectable or metastatic NSCLC.
- To explore the correlation of tumor measurements (e.g., single longest diameter or volume) with PFS and OS in previously-treated subjects with NSCLC in subjects receiving MK-3475 in combination with chemotherapy versus chemotherapy alone.
- To investigate other biomarkers that may correlate with tumor response.
Inclusion Criteria
Male/Female subjects with NSCLC ≥ 18 years of age will be enrolled in this trial.
In order to be eligible for participation in this trial, the subject must:
- Have a histologically-confirmed or cytologically confirmed diagnosis of stage IIIB/IV NSCLC.
- Subjects for cohort A, B, C, E, F and G should have received no prior systemic treatment for stage IIIb/IV NSCLC.
- Subjects for cohorts D and H should have received prior treatment for NSCLC which should have been platinum based, unless EGFR mutation or ALK translocation was present. Subjects who are eligible for specific targeted therapy (e.g., EGFR mutation or ALK translocation) should have received prior treatment with the appropriate targeted agents.
- Subjects for cohorts E and F should have confirmed activating EGFR mutation.
- Patients who had disease progression >1yr after completing adjuvant therapy for stage I -IIIA disease are eligible for Cohort A,B,C, G1 and G2, as long as no systemic therapy was given for the recurrent disease.
- Subject must have at least one radiographically measurable lesion as per RECIST 1.1 defined as a lesion that is ≥10 mm in longest diameter or lymph node that is ≥15 mm in short axis imaged by CT scan or MRI
- Be ≥18 and ≤75 years of age on day of signing informed consent.
- Have a life expectancy of at least 3 months.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status (Section 12.4)
- Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
- 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- 4 weeks without transfusions
- Renal
- Serum creatinine OR calculated creatinine clearance (CrCl)a (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subjects with creatinine levels > 1.5 X institutional ULN
- Hepatic
- Serum total bilirubin ≤ ULN
- AST (SGOT) and ALT (SGPT) ≤ 1.5 X ULN
- Alkaline Phosphatase ≤ 2.5 X ULN
- Endocrine
- Thyroid stimulating hormone (TSH) Within normal limits
- Coagulation
- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless the subject is receiving anticoagulant therapy
- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless the subject is receiving anticoagulant therapy
- NOTE: a. Creatinine clearance should be calculated per institutional standard. If no local guideline is available, Creatinine Clearance should be calculated using the Cockcroft-Gault Method: CrCl = [(140-age) * weight (kg) * (0.85 for females only)] / (72 * serum creatinine)b. If TSH is not within normal limits at baseline, the subject will still be eligible if total T3 or free T3 and free T4 are within the normal limits.
- Female subjects must have a negative urine or serum pregnancy test within 72 hours prior to taking study medication if of childbearing potential or be of non-child bearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as (by other than medical reasons):
- ≥45 years of age and has not had menses for greater than 2 years,
- Amenorrheic for < 2 years without a hysterectomy and oophorectomy and an FSH value in the postmenopausal range upon pretrial (screening) evaluation
- Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the subject must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study therapy. Please see Section 5.7.2 for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents.
- If of childbearing potential, female subjects must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study therapy and up to 180 days after last dose of chemotherapeutic agents or TKIs as specified in the protocol. Please see Section 5.7.2 for a list of acceptable birth control methods.
- Male subjects with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through120 days after the last dose of study medication is received and up to 180 days after last dose of chemotherapeutic agents or TKIs as specified in the protocol. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
- Subject has voluntarily agreed to participate by giving written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of MK-3475.
- a) Within 3 weeks of the first dose of trial treatment:
- Has received prior systemic cytotoxic chemotherapy
- Has received antineoplastic biological therapy (e.g., cetuximab)
- Had major surgery
b) Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment
c) Received prior tyrosine kinase inhibitor therapy or completed palliative radiotherapy within 7 days of the first dose of trial treatment.
- Is expected to require any other form of antineoplastic therapy while on study.
- Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
- Patients with clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
- Has a known history of prior malignancy, except if the patient has undergone potentially curative therapy with no evidence of that disease f recurrence or 5 years since initiation of that therapy.
- Note: The time requirement for no evidence of disease for 5 years does not apply to the NSCLC tumor for which a subject is enrolled in the study. The time requirement also does not apply to subjects 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.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication.
- Previously had a severe hypersensitivity reaction to treatment with another mAb.
- Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects on chronic systemic steroids would be excluded from the study.
- 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. Has participated in any other MK-3475 trial and has been treated with MK-3475.
- Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR.
- Has an active infection requiring therapy.
- Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, 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.
- 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).
- Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
- Has a interstitial lung disease or history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
- Subjects in cohorts E and F that require treatment with a strong inhibitor of CYP3A4 will be excluded. They may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to randomization. If a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration.
- Is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.