Lung Cancer, Melanoma
Conditions
Brief summary
This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy (SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who progress on this antibody. Patients with metastatic melanoma will be enrolled after they have progressed on anti-PD-1 therapy. Patients with metastatic NSCLC (previously untreated with anti-PD-1 or anti-PD-L1 therapy) will be enrolled and treated with MK-3475 until they exhibit progression of disease. At this point (when patients have demonstrated progression of disease) a single target lesion will be selected and treated with SBRT, and then MK-3475 will be restarted and continued until there is further progression of disease. The first phase of the study is a radiation dose escalation with a constant dose of MK-3475. The second part of the study includes expansion cohorts of NSCLC and melanoma patients.
Detailed description
The phase 1b portion of the trial is a radiation dose escalation study to determine the maximum tolerated dose (MTD) of SBRT when given to patients previously and subsequently exposed to MK-3475. Because the class of PD-1 inhibitory antibodies conveys a risk of pneumonitis, there will be two parallel dose escalation arms- Arm A will include SBRT targets in the lung parenchyma, and Arm B will be limited to targets outside the lung parenchyma. Each arm will be separately escalated, and two MTDs will be determined. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. The phase 2a portion of the study includes 2 expansion cohorts, for melanoma and NSCLC, with SBRT delivered at the MTD. The primary endpoint of this phase of the study is the overall response rate to post-SBRT MK-3475. Secondary endpoints include determining the time to progression, overall survival, and exploratory biomarkers. IND exempt per FDA. Inclusion/Exclusion Criteria Updated 4/7/2016
Interventions
DRUGMK-3475
200 mg every 2 weeks by IV infusion
RADIATIONStereotactic Body Radiation Therapy (SBRT)
The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction).
Sponsors
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be willing and able to provide written informed consent/assent for the trial. * 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-PD-1 therapy, patients must have received prior PD-1 therapy and have progressed (irPD) by irRC. * Have 2 or more measurable sites of disease as defined by either 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 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 ECOG Performance Scale. * Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 28 days of protocol treatment. Table 1. Adequate Organ Function Laboratory Values (System/Laboratory Value) Hematological * Absolute neutrophil count (ANC) ≥1,500 /mcL * Platelets ≥100,000 / mcL * Hemoglobin ≥9 g/dL Renal * Measured or calculated creatinine\*\* clearance ≤1.5 X upper limit of normal (ULN) * (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN Hepatic * Serum total bilirubin ≤ 1.5 X ULN OR * Direct bilirubin Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN * AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases \*\*(Creatinine clearance should be calculated per institutional standard. ) * 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 should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. * Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
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 (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., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Has received a live vaccine within 30 days prior to the first protocol treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2, Overall Response | up to 12 months | Phase 2 primary endpoint is the overall response count of patients to post-SBRT MK-3475. Overall response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). The following are counts of those that were assessed to have the following responses: Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD), Not Evaluable. |
| Phase 1, Dose-Limiting Toxicity | up to 12 months | Phase 1 primary endpoint will be the presence of a dose limiting toxicity. Maximum tolerated dose will be the highest dose at which there is not a dose limiting toxicity. This could be either 3000 cGy in 5 fractions or 3 fractions. Presented are counts of the maximum tolerated of participants per arm. Results are summarized by Lung or Non-Lung targets overall. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy Participants with no prior PD-1 therapy that began in the Phase 1: Lung Targets + MK-3475 and then moved to Phase 2 NSCLC phase of the study. | 10 |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD Participants previously treated with immunotherapy/irPD that began in the Phase 1: Lung Targets + MK-3475 and then moved to Phase 2 NSCLC phase of the study. | 3 |
| Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy Participants no prior PD-1 therapy that began in the Phase 1: Non-Lung Target + MK-3475 and then moved to Phase 2 melanoma phase of the study. | 5 |
| Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD Participants previously treated with immunotherapy/irPD that began in the Phase 1: Non-Lung Target and then moved to Phase 2: melanoma phase of the study. | 6 |
| Phase 2: Pre-SBRT for NSCLC Patients in this portion of Phase 2, never progressed to receive SBRT. | 35 |
| Phase 2: EC: Melanoma With Prior PD1 Phase 2a expansion cohort for patients with melanoma. Patients will be treated at the maximum tolerated dose discovered in phase I.
Drug: MK-3475 200 mg every 2 weeks by IV infusion
Radiation: Stereotactic Body Radiation Therapy (SBRT) The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). | 2 |
| Total | 61 |
Baseline characteristics
| Characteristic | Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Total | Phase 2: EC: Melanoma With Prior PD1 | Phase 2: Pre-SBRT for NSCLC | Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD | Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy | Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 13.7 | 67.1 years STANDARD_DEVIATION 10.6 | 65.0 years STANDARD_DEVIATION 7.1 | 67.6 years STANDARD_DEVIATION 10.5 | 59.5 years STANDARD_DEVIATION 6.4 | 67.8 years STANDARD_DEVIATION 6.7 | 74.3 years STANDARD_DEVIATION 13.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 58 Participants | 2 Participants | 32 Participants | 6 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 57 Participants | 2 Participants | 32 Participants | 6 Participants | 4 Participants | 3 Participants |
| Region of Enrollment United States | 10 participants | 60 participants | 2 participants | 35 participants | 6 participants | 5 participants | 3 participants |
| Sex: Female, Male Female | 8 Participants | 36 Participants | 0 Participants | 19 Participants | 5 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 25 Participants | 2 Participants | 16 Participants | 1 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 3 | 1 / 5 | 0 / 6 | 3 / 35 | 0 / 2 |
| other Total, other adverse events | 10 / 10 | 3 / 3 | 5 / 5 | 6 / 6 | 35 / 35 | 2 / 2 |
| serious Total, serious adverse events | 5 / 10 | 0 / 3 | 1 / 5 | 1 / 6 | 13 / 35 | 0 / 2 |
Outcome results
Primary
Phase 1, Dose-Limiting Toxicity
Phase 1 primary endpoint will be the presence of a dose limiting toxicity. Maximum tolerated dose will be the highest dose at which there is not a dose limiting toxicity. This could be either 3000 cGy in 5 fractions or 3 fractions. Presented are counts of the maximum tolerated of participants per arm. Results are summarized by Lung or Non-Lung targets overall.
Time frame: up to 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 1, Dose-Limiting Toxicity | 3000 cGy in 5 fractions | 7 Participants |
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 1, Dose-Limiting Toxicity | 3000 cGy in 3 fractions | 6 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 1, Dose-Limiting Toxicity | 3000 cGy in 5 fractions | 4 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 1, Dose-Limiting Toxicity | 3000 cGy in 3 fractions | 7 Participants |
Primary
Phase 2, Overall Response
Phase 2 primary endpoint is the overall response count of patients to post-SBRT MK-3475. Overall response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). The following are counts of those that were assessed to have the following responses: Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD), Not Evaluable.
Time frame: up to 12 months
Population: Only those that received SBRT.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 2, Overall Response | Progressive disease (PD) | 5 Participants |
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 2, Overall Response | Partial response (PR) | 1 Participants |
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 2, Overall Response | Complete response (CR) | 0 Participants |
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 2, Overall Response | Not Evaluable | 0 Participants |
| Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy | Phase 2, Overall Response | Stable disease (SD) | 4 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Partial response (PR) | 0 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Progressive disease (PD) | 3 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Complete response (CR) | 0 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Not Evaluable | 0 Participants |
| Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Stable disease (SD) | 0 Participants |
| Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Partial response (PR) | 0 Participants |
| Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Progressive disease (PD) | 1 Participants |
| Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Not Evaluable | 2 Participants |
| Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Stable disease (SD) | 2 Participants |
| Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Complete response (CR) | 0 Participants |
| Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Stable disease (SD) | 2 Participants |
| Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Complete response (CR) | 0 Participants |
| Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Partial response (PR) | 0 Participants |
| Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Progressive disease (PD) | 3 Participants |
| Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD | Phase 2, Overall Response | Not Evaluable | 1 Participants |
| Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Progressive disease (PD) | 0 Participants |
| Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Complete response (CR) | 0 Participants |
| Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Not Evaluable | 0 Participants |
| Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Partial response (PR) | 0 Participants |
| Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy | Phase 2, Overall Response | Stable disease (SD) | 0 Participants |
| Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD | Phase 2, Overall Response | Complete response (CR) | 0 Participants |
| Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD | Phase 2, Overall Response | Progressive disease (PD) | 1 Participants |
| Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD | Phase 2, Overall Response | Partial response (PR) | 0 Participants |
| Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD | Phase 2, Overall Response | Not Evaluable | 0 Participants |
| Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD | Phase 2, Overall Response | Stable disease (SD) | 1 Participants |