Study of MK-1697 in Participants With Advanced Solid Tumors (MK-1697-001)

• ClinicalTrials.gov Identifier: NCT03515824
• Recruitment Status: Terminated
• First Posted: May 4, 2018
• Results First Posted: February 12, 2021
• Last Update Posted: March 9, 2021
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and preliminary efficacy of MK-1697. There are 2 parts in this study: dose escalation to determine the recommended phase 2 dose (RP2D) and confirm the RP2D (Part A) and cohort expansion to determine preliminary efficacy in participants with colorectal cancer (CRC) or head and neck squamous cell cancer (HNSCC) (Part B). No formal hypothesis testing will be done in this study.

Condition or disease	Intervention/treatment	Phase
Neoplasms; Colorectal Neoplasms; Head and Neck Neoplasms	Biological: MK-1697	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of MK-1697 in Participants With Advanced Solid Tumors
• Actual Study Start Date: August 13, 2018
• Actual Primary Completion Date: February 18, 2020
• Actual Study Completion Date: February 18, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: MK-1696 20 mg; Participants received 20 mg of MK-1697 by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 administrations (up to approximately 2 years).	Biological: MK-1697; Administered by IV infusion on Day 1 of each 21-day cycle
Experimental: Part A: MK-1697 65 mg; Participants received 65 mg of MK-1697 by IV infusion on Day 1 of each 21-day cycle for up to 35 administrations (up to approximately 2 years).	Biological: MK-1697; Administered by IV infusion on Day 1 of each 21-day cycle
Experimental: Part A: MK-1697 200 mg; Participants received 200 mg of MK-1697 by IV infusion on Day 1 of each 21-day cycle for up to 35 administrations (up to approximately 2 years).	Biological: MK-1697; Administered by IV infusion on Day 1 of each 21-day cycle
Experimental: Part B: Expansion Cohort; Participants with select tumor types were to receive MK-1697 at the RP2D by IV infusion on Day 1 of each 21-day cycle for up to 35 administrations (up to approximately 2 years).	Biological: MK-1697; Administered by IV infusion on Day 1 of each 21-day cycle

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 [ Time Frame: Up to 21 days of Cycle 1 (cycle length = 21 days) ]
   The following toxicities were considered a DLT, if assessed as related to study treatment: Grade (Gr) 4 non-hematologic toxicity (T); Gr 4 hematologic T for ≥7 days; Gr 4 thrombocytopenia; Gr 3 thrombocytopenia with bleeding; ≥Gr 3 non-hematologic clinical AE except fatigue for ≤3 days, Gr 3 nausea, vomiting, or diarrhea for >72 hours despite anti-emetics/diarrheals, or other supportive care; Gr 3 rash without corticosteroids/anti-inflammatory agents use per standard of care; Gr 3/4 non-hematologic laboratory value if: medical intervention is required, abnormality leads to hospitalization, persists for >1 week, or abnormality results in drug-induced liver injury; Gr 3 or 4 febrile neutropenia; treatment-related T causing discontinuation; inability to administer ≥75% of planned dose due to drug-related tolerability; Gr 5 T; delay in Cycle 2 start by >2 weeks due to T. Pool-adjacent violators algorithm was used to estimate DLT rate & Bayesian method for 80% confidence intervals (CIs).
2. Number of Participants Who Experienced At Least One Adverse Event (AE) [ Time Frame: Up to approximately 9 months ]
   An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experienced at least one AE were presented.
3. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) [ Time Frame: Up to approximately 8 months ]
   An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who discontinued study intervention due to an AE were presented.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 18 months (through End of Trial data cut-off 18 Feb 2020) ]
   An objective response was defined as a complete response (CR: Disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by the investigator based on RECIST 1.1 following administration of MK-1697. ORR was reported as percentage of participants who experienced an CR or PR after administration of MK-1967. The exact method based on the binomial distribution (Clopper-Pearson interval) was used to estimate ORR and its associated 95%CIs.
2. Objective Response Rate (ORR) Per Modified Response Evaluation Criteria In Solid Tumors Version 1.1 for Immune-based Therapeutics (iRECIST) [ Time Frame: Up to approximately 18 months (through End of Trial data cut-off 18 Feb 2020) ]
   An objective response was defined as an immune-based complete response (iCR: Disappearance of all target lesions) or immune-based partial response (iPR: At least a 30% decrease in the sum of diameters of target lesions). ORR was reported as percentage of participants who experienced an iCR or iPR after administration of MK-1967. Participants were initially assessed for progressive disease (PD : ≥20% increase in sum of diameters [SD] of target lesions or relative increase of 20%, sum must demonstrate an absolute increase of ≥5 mm or appearance of one/more new lesions) per RECIST 1.1 by local site investigator; later verified by central imaging vendor. Investigator could elect to continue treatment and tumor assessment repeated 4-8 weeks later to confirm PD by iRECIST. The exact method based on the binomial distribution (Clopper-Pearson interval) was used to estimate ORR and its associated 95%CIs.
3. Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC 0-inf) of MK-1697 [ Time Frame: Cycle 1-3: Days 1, 2 (only Cycle 1), 3, 8, 15 - predose and postdose at 10 minutes, 2 hours (cycle length = 21 days) ]
   Serum samples were collected at specified time points for determination of MK-1697 AUC 0-inf. AUC 0-inf was defined as the area under the concentration-time curve of MK-1697 from time zero to infinity for all participants in Part A for each dose group.
4. Area Under the Concentration Time Curve From Time Zero to Last Concentration (AUC 0-last) Measured of MK-1697 [ Time Frame: Cycles 1, 2, and 3: predose, 10 minutes and 2 hours post-dose (cycle length = 21 days) ]
   Serum samples were collected at specified time points for determination of AUC 0-last of MK-1697. AUC 0-last was defined as the area under the concentration-time curve of MK-1697 from time zero to the last concentration of MK-1697 measured for all participants in Part A for each dose group.
5. Maximum Serum Concentration (Cmax) of MK-1697 [ Time Frame: Cycle 1-3: Days 1, 2 (only Cycle 1), 3, 8, 15 - predose and postdose at 10 minutes, 2 hours (cycle length = 21 days) ]
   Serum samples were collected at specified time points for determination of MK-1697 Cmax. Cmax was defined as the maximum concentration of MK-1697 reached for all participants in Part A for each dose group.
6. Minimum Serum Concentration (Cmin) of MK-1697 [ Time Frame: Cycles 1-3, 5, 7, 11: Days 1, 2 (only Cycle 1), 3, 8, 15 - predose and postdose at 10 minutes, 2 hours (cycle length = 21 days) ]
   Serum samples were collected pre-dose at specified time points (Cycles 1, 2, 3, 5, 7, and 11) for the determination of MK-1697 Ctrough (may also be referred to as Cmin) per protocol. Ctrough was defined as the lowest concentration of MK-1697 reached before the next dose was administered. Serum Ctrough of MK-1697 was reported for all participants in Part A for each dose group.

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:

• For Part A; has a histologically- or cytologically-confirmed advanced/metastatic solid tumor and has received, been intolerant to, or been ineligible for all treatments known to confer clinical benefit

• For Part B: has 1 of the following histologically or cytologically confirmed tumor types that are anti-programmed cell death protein 1 (anti PD-1)/anti-programmed death-ligand 1 (anti PD-L1) treatment naive:

  • CRC originating in either the colon or rectum that is locally advanced unresectable or metastatic (ie, Stage IV) and that has received, and progressed on, all available standard-of-care therapies including fluoropyrimidine, oxaliplatin, and irinotecan
  • HNSCC that is considered incurable by local therapies. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Participants may not have a primary tumor site of nasopharynx (any histology). Also, participants must have progressed after receiving platinum-containing systemic therapy
• Has measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)
• Has an evaluable baseline tumor sample (either a recent or archival) for analysis
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Has central venous access (eg, portacath, Hickman line, or peripherally inserted central catheter [PICC] line) currently inserted or be considered medically fit for and willing to undergo the insertion of such a device
• Is not pregnant or breastfeeding
• Female participants of childbearing potential must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment
• Male participants must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period

Exclusion Criteria:

• Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years with the exception of participants who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer, or other in-situ cancers
• Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has had a severe hypersensitivity reaction to treatment with any monoclonal antibody and/or components of the study treatment
• Has an active infection requiring therapy
• Has a history of interstitial lung disease
• Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has known human immunodeficiency virus (HIV) and/or Hepatitis B or C infections, or known to be positive for Hepatitis B antigen/Hepatitis B virus deoxyribonucleic acid (DNA) or Hepatitis C Antibody or ribonucleic acid (RNA)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with participation, make administration of the study treatments hazardous, or make it difficult to monitor adverse effects in the opinion of the treating investigator
• Has a history or current evidence of severe cardiovascular disease, ie, arrhythmias requiring chronic treatment, congestive heart failure (New York Heart Association [NYHA] Class III or IV) or symptomatic ischemic heart disease.
• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• 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
• Has known microsatellite instability (MSI) high or mismatch repair genes (MMR) deficient colorectal cancer. If a participant's MSI status is unknown, a paired blood sample for MSI in addition to biomarker testing is required to determine MSI status retrospectively (for the CRC expansion cohort only)
• Has a positive pregnancy test within 72 hours before the first dose of study treatment
• 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 to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any adverse events that were due to cancer therapeutics administered more than 4 weeks earlier
• Has received prior therapy with an anti-Lymphocyte-activation gene 3 (LAG-3) agent
• Has received a live vaccine within 30 days prior to the first dose of study drug
• Has undergone a prior stem cell or bone marrow transplant within the last 5 years
• Is expected to require any other form of antineoplastic therapy while on study
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment

Contacts and Locations

Locations

Australia, New South Wales

Scientia Clinical Research ( Site 0100)

Randwick, New South Wales, Australia, 2031

Hong Kong

Queen Mary Hospital ( Site 0200)

Hong Kong, Hong Kong

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol and Statistical Analysis Plan  [PDF] May 23, 2019

More Information

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03515824
• Other Study ID Numbers: 1697-001; MK1697-001 ( Other Identifier: Merck )
• First Posted: May 4, 2018
• Results First Posted: February 12, 2021
• Last Update Posted: March 9, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme LLC:

Programmed Cell Death Receptor 1 (PD-1); Programmed Cell Death Receptor Ligand 1 (PD-L1); PD-1; PDL1; PD-L1

Additional relevant MeSH terms:

Neoplasms; Colorectal Neoplasms; Head and Neck Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases