Study of MK-5890 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Adults With Advanced Solid Tumors (MK-5890-001)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03396445

Collaborator

(none)

202

Enrollment

Locations

Arms

80.2

Anticipated Duration (Months)

11.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and pharmacokinetics of MK-5890 when administered alone and in combination with pembrolizumab (MK-3475) in adults with advanced solid tumors. The initial course of MK-5890 monotherapy or MK-5890 plus pembrolizumab combination therapy will be for up to 35 administrations (approximately 2 years). The safety and pharmacokinetics of MK-5890 when administered with pembrolizumab, pemetrexed and carboplatin in adults with nonsquamous non-small cell lung cancer (NSCLC) and MK-5890 when administered with pembrolizumab and nab-paclitaxel in adults with triple-negative breast cancer (TNBC) will also be assessed.

Condition or Disease	Intervention/Treatment	Phase
Pharmacokinetics Solid Tumor Carcinoma, Non-Small-Cell Lung Triple Negative Breast Neoplasms	Drug: MK-5890 Biological: Pembrolizumab Drug: Pemetrexed Drug: Carboplatin Drug: Nab-paclitaxel	Phase 1

Detailed Description

Participants receiving MK-5890 monotherapy who experience disease progression may be eligible to switch to receiving MK-5890 plus pembrolizumab combination therapy for up to 35 cycles (approximately 2 years) at the discretion of the Investigator and approval of the Sponsor.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

202 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Study of MK-5890 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors

Actual Study Start Date :

Feb 18, 2018

Anticipated Primary Completion Date :

Oct 25, 2024

Anticipated Study Completion Date :

Oct 25, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: MK-5890 Participants receive escalating doses of MK-5890 via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years).	Drug: MK-5890 IV infusion
Experimental: Arm 2: MK-5890 + Pembrolizumab Participants receive escalating doses of MK-5890 via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years).	Drug: MK-5890 IV infusion Biological: Pembrolizumab IV infusion Other Names: MK-3475
Experimental: Arm 3: MK-5890 + Pembrolizumab + Pemetrexed + Carboplatin Participants receive MK-5890 at the selected dose via IV infusion PLUS pembrolizumab 200 mg via IV infusion PLUS pemetrexed 500 mg/m^2 via IV infusion PLUS carboplatin Area Under the Curve (AUC) 5 mg/mL/min via IV infusion, all given on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years).	Drug: MK-5890 IV infusion Biological: Pembrolizumab IV infusion Other Names: MK-3475 Drug: Pemetrexed IV infusion Other Names: ALIMTA® Drug: Carboplatin IV infusion Other Names: PARAPLATIN®
Experimental: Arm 4: MK-5890 +Pembrolizumab + Nab-paclitaxel Participants receive MK-5890 at the selected dose via IV infusion PLUS pembrolizumab via IV infusion PLUS nab-paclitaxel 100 mg/m^2 via IV infusion. MK-5890 and pembrolizumab will be given on Day 1 of each 6-week cycle (Q6W). Nab-paclitaxel will be given on a 3-week on (Days 1, 8 and 15)/ 1-week off schedule every 28 days. MK-5890 and pembrolizumab will be given for up to a total of 18 cycles (approximately 2 years).	Drug: MK-5890 IV infusion Biological: Pembrolizumab IV infusion Other Names: MK-3475 Drug: Nab-paclitaxel IV infusion Other Names: ABRAXANE®

Outcome Measures

Primary Outcome Measures

Arms 1 and 2: Dose-limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 or Later [Cycle 1 (Up to 21 days)]
A DLT is defined as any of the following toxicities, if assessed by the investigator to be related to study treatment: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia associated with bleeding that requires a platelet transfusion; Nonhematologic adverse event (AE) Grade ≥3 in severity, with exceptions; Grade 3 or 4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required or if abnormality leads to hospitalization, persists for >1 week or results in drug-induced liver injury with exceptions; Grade 3 or 4 febrile neutropenia; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Treatment-related toxicity resulting in study treatment discontinuation during Cycle 1; Missing >25% of any study drug during the DLT evaluation period as a result of a drug-related AE; Grade 5 toxicity.
Arms 1 and 2: Number of Participants with Adverse Events (AEs) [Up to 27 months]
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Arms 1 and 2 who experience at least one AE will be presented.
Arms 1 and 2: Number of Study Treatment Discontinuations Due to an Adverse Event (AE) [Up to 24 months]
The number of participants in Arms 1 and 2 who discontinue study treatment due to an AE will be presented.

Secondary Outcome Measures

All Arms: Area Under the Concentration-Time Curve (AUC) of MK-5890 [At designated time points (Up to 25 months)]
Blood samples will be obtained at designated time points for the assessment of MK-5890 AUC: Cycles 1-4: Day 1: Predose, (end of pembrolizumab infusion for participants receiving pembrolizumab), end of MK-5890 infusion, 2 hours post start of MK-5890 infusion, Days 2, 3, 5, 8 & 15: Once daily; Cycles 5, 6 & every 4 cycles thereafter: Day1: Predose; 30 days post last dose. Each cycle is 21 days. (Up to 25 months)
All Arms: Minimum Serum Concentration (Cmin) of MK-5890 [At designated time points (Up to 25 months)]
Blood samples will be obtained at designated time points for the assessment of MK-5890 Cmin: Cycles 1-4: Day 1: Predose, (end of pembrolizumab infusion for participants receiving pembrolizumab), end of MK-5890 infusion, 2 hours post start of MK-5890 infusion, Days 2, 3, 5, 8 & 15: Once daily; Cycles 5, 6 & every 4 cycles thereafter: Day1: Predose; 30 days post last dose. Each cycle is 21 days. (Up to 25 months)
All Arms: Maximum Serum Concentration (Cmax) of MK-5890 [At designated time points (Up to 25 months)]
Blood samples will be obtained at designated time points for the assessment of MK-5890 Cmax: Cycles 1-4: Day 1: Predose, (end of pembrolizumab infusion for participants receiving pembrolizumab), end of MK-5890 infusion, 2 hours post start of MK-5890 infusion, Days 2, 3, 5, 8 & 15: Once daily; Cycles 5, 6 & every 4 cycles thereafter: Day1: Predose; 30 days post last dose. Each cycle is 21 days. (Up to 25 months)
Arms 1, 2, and 4: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Up to 24 months]
The ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The ORR of MK-5890 when used as monotherapy, in combination with pembrolizumab (Arms 1 and 2), and in combination with pembrolizumab PLUS nab-paclitaxel (Arm 4) as assessed by the investigator will be presented.
Arm 3: Dose-limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 or Later [Cycle 1 (Up to 21 days)]
A DLT is defined as any of the following toxicities, if assessed by the investigator to be related to study treatment: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia associated with bleeding that requires a platelet transfusion; Nonhematologic adverse event (AE) Grade ≥3 in severity, with exceptions; Grade 3 or 4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required or if abnormality leads to hospitalization, persists for >1 week or results in drug-induced liver injury with exceptions; Grade 3 or 4 febrile neutropenia; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Treatment-related toxicity resulting in study treatment discontinuation during Cycle 1; Missing >25% of any study drug during the DLT evaluation period as a result of a drug-related AE; Grade 5 toxicity.
Arm 4: Dose-limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 or Later [Cycle 1 (Up to 28 days)]
A DLT is defined as any of the following toxicities, if assessed by the investigator to be related to study treatment: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia associated with bleeding that requires a platelet transfusion; Nonhematologic adverse event (AE) Grade ≥3 in severity, with exceptions; Grade 3 or 4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required or if abnormality leads to hospitalization, persists for >1 week or results in drug-induced liver injury with exceptions; Grade 3 or 4 febrile neutropenia; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Treatment-related toxicity resulting in study treatment discontinuation during Cycle 1; Missing >25% of any study drug during the DLT evaluation period as a result of a drug-related AE; Grade 5 toxicity.
Arms 3 and 4: Number of Participants with Adverse Events (AEs) [Up to 27 months]
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Arms 3 and 4 who experience at least one AE will be presented.
Arms 3 and 4: Number of Study Treatment Discontinuations Due to an Adverse Event (AE) [Up to 24 months]
The number of participants in Arms 3 and 4 who discontinue study treatment due to an AE will be presented.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Arms 1 & 2: Histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and has received or been intolerant to all treatment known to confer clinical benefit
Arm 3: Histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b per current American Joint Committee on Cancer criteria) non-squamous NSCLC
Arm 4: Triple-negative breast cancer (TNBC) that is locally recurrent, inoperable, not previously treated with chemotherapy, and which cannot be treated with curative intent OR metastatic disease not previously treated with chemotherapy
Measurable disease by RECIST 1.1. as assessed by the local site investigator/radiologist. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
Adequate organ function
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Male participants must agree to use adequate contraception during the treatment period and for at least 120 days after the last dose of MK-5890 or pembrolizumab OR 180 days after the last dose of chemotherapeutic agents and refrain from donating sperm during this period
Female participants must not be pregnant or breastfeeding and agree to follow use adequate contraception during the treatment period and for at least 120 days after the last dose of MK-5890 or pembrolizumab OR 180 days after the last dose of chemotherapeutic agents
Submit an evaluable baseline tumor sample for analysis (either a newly obtained or archival tumor sample)

Exclusion Criteria:

History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
Clinically active central nervous system metastases and/or carcinomatous meningitis
Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb) and/or other components of the study treatment
Active infection requiring systemic treatment
History of interstitial lung disease
History of (noninfectious) pneumonitis that required steroids or current pneumonitis
Symptomatic ascites or pleural effusion
Previously had a stem cell or bone marrow transplant
Previously had a solid organ transplant
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy
Known human immunodeficiency virus (HIV) and/or active and acute Hepatitis B or C infections
Not fully recovered from any effects of major surgery without significant detectable infection
Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
Had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) before the first dose of study treatment, or has not recovered to Grade ≤1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier
Expected to require any other form of antineoplastic therapy while participating in this study
On chronic systemic steroid therapy in excess of replacement doses (e.g., exceeding 10 mg/day of prednisone equivalent), or on any other form of immunosuppressive medication
Regular user (including "recreational use") of any illicit drugs at the time of signing informed consent, or has a recent history (within the last year) of substance abuse (including alcohol), as determined by the treating investigator. Participants who use cannabis for medicinal purposes or to treat specific symptoms will not be excluded unless it is being abused in the opinion of the treating investigator
Received a live-virus vaccine within 28 days before the first dose of study treatment
Currently participating and receiving study treatment in a study of an investigational agent or has participated and received study treatment in a study of an investigational agent or has used an investigational device within 28 days before the first dose of study treatment

Additional Exclusion Criteria for Participants in Arm 3:

Has received radiation therapy to the lung that is >30 Gray (Gy) within 6 months before the first dose of study treatment
Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
Is unable or unwilling to take folic acid or vitamin B12 supplementation

Additional Exclusion Criteria for Participants in Arm 4:

Has a known history of hypersensitivity or allergy to nab-paclitaxel or any of its components
Has neuropathy ≥Grade 2
Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months of randomization
Has received previous treatment with immune checkpoint inhibitor(s) (eg, Programmed Cell Death Receptor 1 (PD-1)/PD-L1)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama, Mitchell Cancer Institute ( Site 0020)	Mobile	Alabama	United States	36604
2	Florida Cancer Specialists ( Site 0002)	Sarasota	Florida	United States	34232
3	The West Clinic, P.C. ( Site 0021)	Germantown	Tennessee	United States	38138
4	FALP-UIDO ( Site 0502)	Santiago	Region M. De Santiago	Chile	6900941
5	Bradfordhill-Clinical Area ( Site 0501)	Santiago	Region M. De Santiago	Chile	8420383
6	Soroka Medical Center-Oncology ( Site 0012)	Be'er Sheva		Israel	8400000
7	Hadassah Ein Kerem Medical Center ( Site 0010)	Jerusalem		Israel	9112001
8	The Chaim Sheba Medical Center - Oncology Institute ( Site 0001)	Ramat Gan		Israel	5265601
9	Seoul National University Hospital-Internal Medicine ( Site 0702)	Seoul		Korea, Republic of	03080
10	Severance Hospital, Yonsei University Health System-Medical oncology ( Site 0701)	Seoul		Korea, Republic of	03722
11	Antoni van Leeuwenhoek Ziekenhuis ( Site 0003)	Amsterdam	Noord-Holland	Netherlands	1066 CX
12	Erasmus MC ( Site 0031)	Rotterdam	Zuid-Holland	Netherlands	3015 GD
13	Hospital Universitario Fundacion Jimenez Diaz ( Site 0041)	Madrid	Madrid, Comunidad De	Spain	28040
14	Hospital Universitario Quiron Madrid ( Site 0043)	Pozuelo de Alarcon	Madrid	Spain	28223
15	Instituto Catalan de Oncologia - ICO ( Site 0044)	Barcelona		Spain	08916
16	Centro Integral Oncologico Clara Campal START Madrid ( Site 0040)	Madrid		Spain	28050
17	National Taiwan University Hospital-Oncology ( Site 0801)	Taipei		Taiwan	10002
18	Koo Foundation Sun Yat-Sen Cancer Center ( Site 0802)	Taipei		Taiwan	112