Study of CM-24 (MK-6018) Alone and In Combination With Pembrolizumab (MK-3475) in Participants With Selected Advanced or Recurrent Malignancies (MK-6018-001)

• ClinicalTrials.gov Identifier: NCT02346955
• Recruitment Status: Terminated
• First Posted: January 27, 2015
• Last Update Posted: March 16, 2017
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and tolerability of humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 (CM-24 [MK-6018]), administered intravenously as monotherapy and in combination with Pembrolizumab (MK-3475), in participants with selected advanced or recurrent malignancies. Escalating multiple doses will be evaluated to determine the recommended dose for Phase 2 clinical studies.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Carcinoma (NSCLC); Melanoma; Bladder Cancer; Colorectal Cancer; Gastric Cancer; Ovarian Cancer	Biological: CM-24 (MK-6018); Biological: Pembrolizumab (MK-3475)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-Label, Multicenter, Multi-Dose Escalation Study of CM-24 (MK-6018) as Monotherapy and In Combination With Pembrolizumab (MK-3475) in Subjects With Selected Advanced or Recurrent Malignancies
• Study Start Date: February 2015
• Actual Primary Completion Date: February 2017
• Actual Study Completion Date: February 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A Monotherapy Dose Escalation; Participants will be enrolled in a staggered manner starting at a dose of 0.01 mg/kg of CM-24 (MK-6018) and continuing to 0.03, 0.1, 0.3, 1.0, 3.0, and 10 mg/kg to determine the recommended Phase 2 dose (RP2D). The dose will be escalated after a 6- to 8-week DLT window. Participants will be treated for 12 weeks during Cycle 1. Afterwards participants with clinical benefit and no dose-limiting toxicites (DLTs) are treated for up to 6 cycles.	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1
Experimental: Cohort B Combination Dose Escalation; Participants will be enrolled at the recommended phase 2 dose (RP2D) of CM-24 (MK-6018), determined by escalation studies, minus 1 dose level of MK-6018 in combination with a fixed dose of 200 mg pembrolizumab. Participants will be escalated to the RP2D of MK-6018 + 200 mg pembrolizumab. If the RP2D of MK-6018 + 200 mg pembrolizumab is not tolerated, the dose of MK-6018 will be de-escalated but will not fall below 1 mg/kg. Participants will be treated for 6 weeks during Cycle 1 and 2. Afterwards participants with clinical benefit and no DLTs are treated for up to 35 cycles.	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1; Biological: Pembrolizumab (MK-3475); 200 mg of Pembrolizumab by IV infusion; Other Name: KEYTRUDA®
Experimental: Cohort C Monotherapy Expansion; Participants with advanced or recurrent cutaneous melanoma will be enrolled and treated at the recommended phase 2 dose of CM-24 (MK-6018) for up to 17 cycles.	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1
Experimental: Cohort D Monotherapy Expansion; Participants with advanced or recurrent colorectal cancer will be enrolled and treated at the recommended phase 2 dose of CM-24 (MK-6018) for up to 17 cycles.	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1
Experimental: Cohort E Monotherapy Expansion; Participants with advanced or recurrent gastric cancer will be enrolled and treated at the recommended phase 2 dose of CM-24 (MK-6018) for up to 17 cycles.	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1
Experimental: Cohort C1 Combination Expansion; Participants with advanced or recurrent cutaneous melanoma will be enrolled and treated at the recommended phase 2 dose of CM-24+ 200 mg of Pembrolizumab for up to 17 cycles and may continue to receive 200 mg of Pembrolizumab as monotherapy for up to an additional 18 cycles (up to 35 total cycles).	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1; Biological: Pembrolizumab (MK-3475); 200 mg of Pembrolizumab by IV infusion; Other Name: KEYTRUDA®
Experimental: Cohort D1 Combination Expansion; Participants with advanced or recurrent colorectal cancer will be enrolled and treated at the recommended phase 2 dose of CM-24+ 200 mg of Pembrolizumab for up to 17 cycles and may continue to receive 200 mg of Pembrolizumab as monotherapy for up to an additional 18 cycles (up to 35 total cycles).	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1; Biological: Pembrolizumab (MK-3475); 200 mg of Pembrolizumab by IV infusion; Other Name: KEYTRUDA®
Experimental: Cohort E1 Combination Expansion; Participants with advanced or recurrent gastric cancer will be enrolled and treated at the recommended phase 2 dose of CM-24+ 200 mg of Pembrolizumab for up to 17 cycles and may continue to receive 200 mg of Pembrolizumab as monotherapy for up to an additional 18 cycles (up to 35 total cycles).	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1; Biological: Pembrolizumab (MK-3475); 200 mg of Pembrolizumab by IV infusion; Other Name: KEYTRUDA®
Experimental: Cohort F Combination Expansion; Participants with advanced or recurrent non-small cell lung adenocarcinoma will be enrolled and treated at the recommended phase 2 dose of CM-24+ 200 mg of Pembrolizumab for up to 17 cycles and may continue to receive 200 mg of Pembrolizumab as monotherapy for up to an additional 18 cycles (up to 35 total cycles).	Biological: CM-24 (MK-6018); humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 by intravenous (IV) infusion; Other Name: Anti-CEACAM1; Biological: Pembrolizumab (MK-3475); 200 mg of Pembrolizumab by IV infusion; Other Name: KEYTRUDA®

Outcome Measures

Primary Outcome Measures :

1. Number of participants with Adverse Events (AEs) [ Time Frame: From time of first dose until the end of follow-up (up to 123 weeks) ]
2. Number of participants discontinuing study drug due to AEs [ Time Frame: From time of first dose until the end of follow-up (up to 105 weeks) ]
3. Number of participants with a Dose Limiting Toxicity (DLT) [ Time Frame: From time of first dose until the end of follow-up (up to 12 weeks) ]

Secondary Outcome Measures :

1. Maximum drug concentration in serum/plasma (Cmax) [ Time Frame: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion. ]
2. Time to reach Cmax in serum/plasma (Tmax) [ Time Frame: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion. ]
3. Terminal-phase elimination half-life in serum/plasma (t1/2) [ Time Frame: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion. ]
4. Area under the plasma/serum concentration versus time curve from time zero to the last measured time (AUC 0-T) [ Time Frame: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion. ]
5. Area under the plasma/serum concentration versus time curve from time zero to infinity (AUC 0-∞) [ Time Frame: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion. ]
6. Objective Response Rate (ORR) defined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [ Time Frame: From time of screening until the end of follow-up (up to 123 weeks) ]
7. Time from ORR to disease progression or death (DOR) [ Time Frame: From time of screening until the end of follow-up (up to 123 weeks) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males and females ≥18 years of age
• Participants in the Dose Escalation portion must have one of the following advanced or recurrent malignancies: gastrointestinal (colorectal or gastric); ovarian; melanoma; non-small cell lung adenocarcinoma; or bladder.
• Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III.
• Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III.
• Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy
• Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy
• Must have adequate hematologic, renal, and liver function
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding
• Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment
• An estimated life expectancy of at least 3 months
• Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit
• Must consent to allow the acquisition of new tissue biopsy samples during the study

Exclusion Criteria:

• History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies
• History of other active malignancy within the prior 2 years
• History of insulin-dependent or uncontrolled Diabetes Mellitus
• History of inflammatory bowel disease
• Autoimmune disorders
• Known HIV and/or Hepatitis B or C infections
• Known systemic bleeding or platelet disorder
• Receipt of live vaccines with 4 weeks (28 days) of study
• History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis

Contacts and Locations

Locations

United States, California

Call for Information (Investigational Site 0003)

Los Angeles, California, United States, 90095

United States, Connecticut

Call for Information (Investigational Site 0004)

New Haven, Connecticut, United States, 06513

Israel

Merck Sharp & Dohme Co. Ltd.

Hod Hasharon, Israel

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT02346955 History of Changes
• Other Study ID Numbers: 6018-001; CB-24-01 ( Registry Identifier: prior cCAM Biotherapeutics Ltd Protocol Number ); MK-6018-001 ( Other Identifier: Merck Registration Number )
• First Posted: January 27, 2015
• Last Update Posted: March 16, 2017
• Last Verified: March 2017

Keywords provided by Merck Sharp & Dohme Corp.:

Cancer; Oncology; cCAM Biotherapeutics Ltd; Immunomodulatory therapy; CM-24; Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1); NSCLC (adenocarcinoma); Uveal; Acral; Mucosal; Cutaneous; Colorectal; Gastric; Ovarian; Bladder; MK-6018-001

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Neoplasms; Neoplasms by Site; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents