A Phase 1 Open-Label, Multi-arm, Multicenter Study of MK-4830 as Monotherapy and in Combination with Pembrolizumab for Participants with Advanced Solid Tumors
Phase 1 Trial of MK-4830 as Monotherapy and Combination with Pembrolizumab
1) Dose escalation participants: Has any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and has received, has been intolerant to, or has been ineligible for all treatment known to confer clinical benefit. Solid tumors of any type are eligible for enrollment.
2) Has measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) as assessed by the local site investigator/radiology.
3) Submits an evaluable baseline tumor sample for analysis (either a recent or archival tumor sample).
4) Dose Escalation Part C and Back-fill participants: Has 1 or more discrete malignant lesions that are amenable to biopsy
5) Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. This inclusion criterion does not apply to Expansion phase Arm B.
6) Demonstrates adequate organ function
7) A male participant must agree to use an approved contraception(s) during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.
8) A female participant is eligible to participate if she is not pregnant, not breastfeeding, and either not a woman of childbearing potential (WOCBP) OR if a WOCBP agrees to follow the study contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment.
9) Expansion phase Arm A participants:
-Has histologically or cytologically confirmed metastatic pancreatic adenocarcinoma.
-Received at least 1 prior line of therapy and no more than 3 prior lines of systemic therapy.
10) Expansion phase Arm B participants:
-Has histologically or cytologically confirmed unresectable GBM or its variants.
-Has a Karnofsky performance status (KPS) >=70.
-Has had no more than 1 prior line of therapy for GBM. Radiation with or without chemotherapy is acceptable as the prior treatment.
-Has shown unequivocal evidence for tumor progression by MRI or CT scan by contrast within 2 weeks prior to randomization.
-Has an interval of at least 3 weeks (to randomization) between prior surgical resection or one week for stereotactic biopsy.
-Has an interval of at least 12 weeks from the completion of radiation therapy to randomization unless there is unequivocal histologic confirmation of tumor progression or radiographic progression outside of the prior radiation field.
-Is neurologically stable (eg, without a progression of neurologic symptoms or requiring escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable.
11) Expansion phase Arm C participants:
-Has histologically confirmed recurrent or metastatic head and neck squamous cell cancer (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies.
-Has experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab.
12) Expansion phase Arm D participants:
-Has histologically confirmed advanced or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies.
-Should not have had any prior PD-1/PD-L1 therapy.
13) Expansion phase Arms E and F participants:
-Has a histologically or cytologically confirmed diagnosis of Advanced (Stage IIIb) or Stage IV metastatic non-small-cell lung cancer (NSCLC).
-Has received no prior systemic therapy for chemotherapy or other targeted or biological antineoplastic therapy treatment for Stage IIIb or Stage IV metastatic NSCLC. Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed if therapy was completed at least 6 months prior to the diagnosis of advanced disease. Participants with prior treatment with an anti-PD-1 or PD-L1 agent are not eligible.
14) Expansion phase Arm G participants:
-Has a histologically or cytologically confirmed diagnosis of Advanced (Stage IIIb) or Stage IV metastatic non-squamous NSCLC (AJCC version 8).
-Is able to tolerate chemotherapy with carboplatin and pemetrexed.
-Has received no prior systemic therapy for advanced NSCLC.
15) Expansion phase Arm H participants:
-Has histologically confirmed diagnosis of renal cell cancer (RCC) with clear cell component with or without sarcomatoid features.
-Has locally advanced/metastatic disease or has recurrent disease.
-Has received no prior systemic therapy for advanced RCC.
16) Expansion phase Arm I participants:
-Has histologically confirmed diagnosis of recurrent and/or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies.
-Has received and progressed on at least two prior chemotherapy regimens.
-If tumor was if HER2/neu positive, participant must have previously received treatment with trastuzumab.
1) Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or has not recovered from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier.
2) Has not recovered from all radiation-related toxicities to Grade 1 or less, requires corticosteroids, and had radiation pneumonitis.
3) Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
4) Has known untreated central nervous system metastases or known carcinomatous meningitis. This exclusion criterion does not apply to Expansion phase Arm B.
5) Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related AEs
6) Previously had a severe hypersensitivity reaction to treatment with a monoclonal antibody or has a known sensitivity to any component of pembrolizumab.
7) Has an active infection requiring therapy.
8) Has a history of interstitial lung disease.
9) Has a history of noninfectious pneumonitis that required steroids or current pneumonitis.
10) Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy.
11) Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure.
12) Known history of human immunodeficiency virus (HIV).
13) Known active hepatitis B or C.
14) Is taking chronic systemic steroids in doses >10 mg daily of prednisone or equivalent within 7 days prior to the first dose of trial treatment.
15) Has not fully recovered from any effects of major surgery without significant detectable infection. Surgeries that required general anesthesia must be completed at least 2 weeks before first study treatment administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study treatment administration and participants should be recovered.
16) Has received a live virus vaccine within 30 days of planned treatment start.
17) Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-4830.
18) All Expansion phase participants:
-Tumor types with known MSI-high status are not eligible.
19) Expansion phase Arm A participants:
-Has received more than 3 lines of prior therapy for advanced disease (pancreatic cancer).
20) Expansion phase Arm B participants:
-Has tumor primarily localized to the brainstem or spinal cord.
-Has presence of diffuse leptomeningeal disease or extracranial disease.
-Has recurrent tumor greater than 6 cm in maximum diameter.
-Requires treatment with moderate or high dose systemic corticosteroids for at least 3 days within 2 weeks of randomization.
21) Expansion phase Arm D participants:
-Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their advanced metastatic HNSCC
22) Expansion phase Arm E and F participants:
-Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their Stage IIIb or Stage IV metastatic (Arms E and F).
23) Expansion phase Arm G participants:
-Has had prior treatment with any anti-PD-1, PD-L1, or programmed cell death-ligand 2 (PD-L2) agent.
24) Expansion phase Arm H participants:
-Has had prior treatment with any anti-PD-1, PD-L1, or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms.
-Has received prior systemic anticancer therapy for RCC.
-Has a clinically significant gastrointestinal (GI) abnormality.
-Has a history of untreated deep vein thrombosis or pulmonary embolism within 6 months prior to screening.
-Has poorly controlled hypertension.
-Has active GI bleeding.
-Has evidence of inadequate wound healing.
-Has active bleeding disorder or other history of significant bleeding episodes within 30 days prior to randomization.
-Has hemoptysis within 6 weeks prior to randomization.
-Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
25) Expansion phase Arm I participants:
-Has experienced weight loss > 10 % over 2 months prior to first dose of study therapy.
-Has clinical evidence of ascites.
-Has peritoneal metastases.
18age old over
No limit
Both
Advanced solid tumor
Dose Escalation, Part A
MK-4830 monotherapy (with MK-4830 doses determined by an accelerated titration design [ATD]) will be administered intravenously (IV), every 3 weeks (Q3W), for a maximum of 35 cycles. Each cycle is 21 days.
Dose Escalation, Part B:
MK-4830 monotherapy (with MK 4830 doses determined by a modified toxicity probability interval [mTPI] method) will be administered IV, Q3W, for a maximum of 35 cycles. Each cycle is 21 days.
Dose Escalation, Part C:
Combination therapy with MK-4830 and pembrolizumab (with MK-4830 doses determined by an mTPI design). MK-4830 will be administered IV, Q3W. Pembrolizumab will be dosed at 200 mg IV Q3W. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles.
Dose Expansion, Arm A to F, and I:
Combination therapy with the preliminary recommended phase 2 dose (RP2D) of MK-4830 and pembrolizumab. MK-4830 will be administered IV, Q3W. Pembrolizumab will be dosed at 200 mg IV Q3W. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles.
Dose Expansion, Arm G:
Combination therapy with the preliminary recommended phase 2 dose (RP2D) of MK-4830, pembrolizumab and Carboplatin/Pemetrexed. MK-4830 will be administered IV, Q3W. Pembrolizumab will be dosed at 200 mg IV Q3W. Carboplatin and pemetrexed will be administered IV Q3W, for 4 cycles, followed by pemetrexed Q3W continuous with MK-4830 and pembrolizumab, up to 35 cycles. Each cycle is 21 days.
Dose Expansion, Arm H:
Combination therapy with the preliminary recommended phase 2 dose (RP2D) of MK-4830, pembrolizumab and Lenvatinib. MK-4830 will be administered IV, Q3W. Pembrolizumab will be dosed at 200 mg IV Q3W. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles. Lenvatinib will be administered orally once daily for up to 35 cycles of 21 days.
1) Dose-limiting toxicities in the dose escalation phase and Arms G and H, AEs and Discontinuations of study treatment due to an AE.
2) In the expansion phase for Arms A through F and I, the objective response rate based on RECIST 1.1 (RANO for Arm B).
MK-4830 pharmacokinetic parameters including AUC, Cmin, and Cmax
