Pembrolizumab and Stereotactic Body Radiation Therapy in Treating Patients with Metastatic Melanoma or Non-small Cell Lung Cancer
This phase Ib /IIa trial studies the side effects and best dose of stereotactic body radiation therapy when given together with pembrolizumab in treating patients with melanoma or non-small cell lung cancer that has spread to other places in the body. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Monoclonal antibodies, such as pembrolizumab, may block specific proteins which may strengthen the immune system and control tumor growth. Giving stereotactic body radiation therapy may prolong the response to pembrolizumab in patients with melanoma or non-small cell lung cancer.
Inclusion Criteria
- Be willing and able to provide written informed consent/assent for the trial
- Be >= 18 years of age on day of signing informed consent
- Have metastatic melanoma or NSCLC, or locally advanced NSCLC not suitable for curative-intent local therapy
- For melanoma patients and NSCLC patients treated with prior anti-programmed cell death protein 1 (PD-1) therapy, patients must have recieed prior PD-1 therapy and have progressed immune-related progressive disease (irPD) by immune-related Response Criteria (irRC)
- Have 2 or more measurable sites of disease as defined by either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or cutaneous lesions at least 1 cm in greatest dimension
- Have at least one site of disease that is considered potentially suitable for treatment with SBRT
- Have provided tissue from an archival or newly obtained tissue sample of a tumor lesion, sufficient for analysis of programmed cell death 1 ligand 1 (PD-L1) and other biomarkers; patients who have had PD-L1 analysis previously performed at Merck can substitute earlier analysis results and are not required to submit additional tissue for PD-L1 testing; expression of PD-L1 is NOT required for study entry
- Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Absolute neutrophil count (ANC) >= 1,500 /mcL (within 28 days of protocol treatment)
- Platelets >= 100,000 /mcL (within 28 days of protocol treatment)
- Hemoglobin >= 9 g/dL (within 28 days of protocol treatment)
- Serum creatinine <= 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 28 days of protocol treatment)
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 28 days of protocol treatment)
- 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 (within 28 days of protocol treatment)
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Male subjects must agree to use an adequate method of contraception starting from the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
Exclusion Criteria
- Has had radiation therapy within 2 weeks of the first protocol treatment
- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first protocol treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks of the first protocol treatment; the use of low-dose steroids for management of chronic conditions is allowed
- Non-small cell lung cancer patients enrolling to MK-3475 as first protocol therapy (no prior anti-PD-1 therapy): Has had a prior monoclonal antibody within 4 weeks prior to first protocol treatment or who has not recovered (i.e., =< Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of the first protocol treatment 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: Patients who have had prior treatments with tyrosine kinase inhibitors (e.g. Tarceva) require only a 72-hour washout period prior to starting protocol treatment
- 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 and untreated brain (central nervous system [CNS]) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate
- 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 example of an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; those with a history of hypothyroidism who are now stable on hormone replacement will not be excluded; those with Sjorgen’s syndrome will not be excluded from the study
- Has a history of (non-infectious) pneumonitis that required steroids, current pneumonitis or evidence of interstitial lung disease
- Has an active infection requiring systemic therapy
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days prior to the first protocol treatment
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02407171.
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) to lung (Arm A) and non-lung (Arm B) targets in patients receiving pembrolizumab (MK-3475). (Phase Ib)
II. To determine the overall response rate to post-radiation MK-3475, in patients whose disease had previously progressed on MK-3475 or another anti-PD-1 therapy. (Phase IIa)
SECONDARY OBJECTIVES:
I. To determine the local control of SBRT, when SBRT is given with MK-3475.
II. To determine the time to progression in patients receiving post-radiation MK-3475, in patients whose disease had previously progressed on MK-3475 or another anti-PD-1 therapy.
III. To determine the progression-free and overall survival in patients MK-3475, who receive SBRT.
IV. To determine the safety and toxicity of the combination of SBRT and MK-3475.
V. To examine potential predictive biomarkers in tumor samples and peripheral blood in patients treated with MK-3475 and SBRT.
OUTLINE: This is a phase Ib, dose-escalation study of SBRT followed by a phase IIa study. Patients are assigned to 1 of 2 arms.
ARM A (NO PRIOR ANTI-PD-1 THERPAY): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for up to 18 months in the absence of disease progression or unacceptable toxicity. After progression of disease, patients undergo SBRT. Patients then receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 18 months in the absence of disease progression or unacceptable toxicity.
ARM B (PRIOR ANTI-PD-1 THERPAY): Patients undergo SBRT. Patients then receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 18 months 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.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationYale University
Principal InvestigatorAllison Campbell
- Primary ID1411014879
- Secondary IDsNCI-2016-00944
- ClinicalTrials.gov IDNCT02407171