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Study to Explore the Safety, Tolerability and Efficacy of MK-3475 in Combination With INCB024360 in Participants With Selected Cancers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02178722
Recruitment Status : Active, not recruiting
First Posted : July 1, 2014
Results First Posted : December 19, 2019
Last Update Posted : December 19, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Incyte Corporation

Brief Summary:
The purpose of this study was to assess the safety, tolerability, and efficacy when combining MK-3475 and INCB024360 in participants with certain cancers. This study was conducted in 2 phases, Phase 1 and Phase 2.

Condition or disease Intervention/treatment Phase
Microsatellite-instability (MSI) High Colorectal Cancer (CRC) Endometrial Cancer Head and Neck Cancer Hepatocellular Carcinoma (HCC) Gastric Cancer Lung Cancer Lymphoma Renal Cell Carcinoma (RCC) Ovarian Cancer Solid Tumors UC (Urothelial Cancer) Melanoma Bladder Cancer Triple Negative Breast Cancer (TNBC) Drug: MK-3475 Drug: INCB024360 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 444 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination With INCB024360 in Subjects With Selected Cancers (ECHO-202/KEYNOTE-037)
Actual Study Start Date : July 17, 2014
Actual Primary Completion Date : November 26, 2018
Estimated Study Completion Date : August 2020


Arm Intervention/treatment
Experimental: Phase 1: MK-3475 + INCB024360
Phase 1: MK-3475 + INCB024360 25 mg twice a day (BID) as starting dose, followed by dose escalations (Phase 1) until recommended phase 2 dose of INCB024360 is determined
Drug: MK-3475
IV infusion

Drug: INCB024360
Oral daily dosing

Experimental: Phase 2: MK-3475 + INCB024360
(recommended phase 2 dose)
Drug: MK-3475
IV infusion

Drug: INCB024360
Oral daily dosing




Primary Outcome Measures :
  1. Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events [ Time Frame: From study start up to clinical data cut-off date of 26 Nov 2018 (approximately 54 months) ]
    An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a participant provides informed consent. A TEAE is any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug. Serious adverse event (SAE) is defined as an event that meets 1 of the following criteria: is fatal or life threatening, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, is clinically meaningful (i.e. defined as an event that jeopardizes the participant or requires potential medical or surgical intervention to prevent 1 of the outcomes listed above) or requires inpatient hospitalization or prolongation of existing hospitalization.

  2. Phase 2: Objective Response Rate (ORR) [ Time Frame: Assessed every 9 weeks after the first dose of study treatment for the first 2 assessments (Weeks 9 and 18) then every 12 weeks thereafter until data cut-off date of 26 Nov 2018 (approximately 54 months) ]
    ORR was proportion of participants with best overall response [complete response (CR) or partial response (PR)], per modified Response Evaluation Criteria In Solid Tumors (irRECIST) v1.1 criteria for select solid tumors or modified Lugano Classification for diffuse large B-cell lymphoma (DLBCL).


Secondary Outcome Measures :
  1. Phase 2: Duration of Response (DOR) [ Time Frame: Assessed every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks ]
    Duration of response is the time from the first overall response contributing to an objective response (complete response or partial response) to the date of death or the date of first overall response of progressive disease (whichever is earliest).

  2. Phase 2: Progression Free Survival (PFS) [ Time Frame: Response is measured every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks ]
    Progression-free survival is defined as number of days from the first day of taking study drug to the earlier of death or disease progression by irRECIST v1.1 for select solid tumors and modified Lugano Classification (Cheson et al 2014) for DLBCL.

  3. Phase 2: Duration of Disease Control [ Time Frame: Assessed every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks ]
    The duration of disease control is the time from the treatment start date to the first objective response of PD (by irRECIST v1.1 or Lugano Classification Cheson et al 2014), death, or last tumor assessment date (if PD/death not present), for subjects with best overall response of SD or bette

  4. Phase 2: Ordinal Categorical Response Score [ Time Frame: Assessed every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks ]

    Ordinal categorical response score, determined by radiographic disease assessments per irRECIST v1.1. The 5-category ordinal response endpoint is determined at a given timepoint by classifying response into one of the following groups:

    1. = Complete response per irRECIST v1.1
    2. = Very good response, defined as > 60% tumor reduction
    3. = Minor response, defined as > 30% to ≤ 60% tumor reduction
    4. = Stable disease per irRECIST v1.1
    5. = Progressive disease per irRECIST v1.1

  5. Phase 2: Overall Survival (OS) [ Time Frame: Patients are checked for survival every 12 weeks for duration of study participation which is estimated to be a minimum of 18 weeks ]
    Overall survival is determined from the date of first dose until death due to any cause.

  6. Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events [ Time Frame: Adverse events are assessed every 3 weeks for duration of study participation which is estimated to be 27 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Subjects with histologically or cytologically non−small cell lung cancer (NSCLC), melanoma, transitional cell carcinoma of the genitourinary (GU) tract, renal cell cancer, triple negative breast cancer, adenocarcinoma of the endometrium or squamous cell carcinoma of the head and neck (Phase 1).
  • Subjects with histologically confirmed melanoma, NSCLC, transitional cell carcinoma of the GU tract, TNBC, SCCHN, ovarian cancer, MSI high colorectal cancer (CRC), RCC, gastric cancer, HCC and DLBCL (Phase 2).
  • Life expectancy > 12 weeks.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1.
  • Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Lugano Classification for subjects with DLBCL.
  • Laboratory and medical history parameters within protocol-defined range.
  • For Phase 1: Subjects who have advanced or metastatic disease as noted above that have received at least one prior therapy or have advanced or metastatic disease for which no curative treatment is available may be enrolled.
  • For Phase 2 expansion cohorts: Subjects with NSCLC, melanoma (checkpoint inhibitor naïve, primary refractory melanoma, relapsed melanoma), transitional cell carcinoma of the GU tract, SCCHN, ovarian cancer, MSI high CRC, RCC, DLBCL, TNBC, gastric cancer, and HCC.

    • Phase 2 expansion: NSCLC

      • Subjects who have received at least 1 prior platinum-based therapy. Subjects who have a non-platinum-based regimen may be enrolled with medical monitor approval.
      • Tumors with epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive treated with a tyrosine kinase inhibitor are permitted; however, subjects should have progressed on or be intolerant to the targeted therapy.
      • Subjects must not have received immunotherapy with programmed death receptor-1 (PD-1) or cytotoxic T-lymphocyte antigen (CTLA-4) targeted therapy.
    • Phase 2 expansion: Melanoma

      • Documentation of V600E-activating BRAF mutation status.
      • Prior systemic therapy requirements.
      • Melanoma immune checkpoint-naïve: Subjects must not have received immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. Exception: Prior anti−CTLA-4 in the adjuvant setting would be permitted.
      • Primary refractory melanoma: Subjects must have received prior treatment with anti-PD-1 or anti-PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and have progressive disease as their best response to treatment that is confirmed 4 weeks later.
      • Relapsed melanoma: Subjects must have received prior anti−PD-1 or anti−PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and achieved partial response ore complete response but later have confirmed progressive disease.
      • Subjects enrolling in the primary refractory or relapsed melanoma must be willing to undergo mandatory pretreatment and on-treatment biopsies.
      • Ocular melanoma is excluded.
    • Phase 2 expansion: Transitional cell carcinoma of the GU tract

      • Metastatic or locally advanced and not amenable to curative therapy with disease progression on or after platinum-based chemotherapy or alternative therapy if platinum-based therapy is not appropriate.
      • Prior PD-1 or CTLA-4 targeted therapies are excluded
    • Phase 2 expansion: SCCHN

      • Histologically confirmed metastatic or recurrent squamous cell carcinoma not amenable to local therapy with curative intent (surgery or radiation with or without chemotherapy). Carcinoma of the nasopharynx, salivary gland, or * *Subjects must have received at least 1 prior systemic chemotherapy regimen that must have included a platinum-based therapy.
      • Prior PD-1 or CTLA-4 targeted therapies are excluded.
    • Phase 2 expansion: Ovarian cancer

      • Subjects with FIGO Stage Ic, Stage II, Stage III, Stage IV, recurrent, or persistent (unresectable) histologically confirmed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma.
      • Subjects must have received a platinum-taxane-based regimen as first-line therapy.
      • Prior PD-1 or CTLA-4 targeted therapies are excluded.
      • Borderline, low-malignant-potential epithelial carcinoma per histopathology is excluded.
    • Phase 2 expansion: Relapsed or refractory DLBCL

      • Prior allogeneic stem-cell transplantation is excluded.
      • Must have received > or = 1 prior treatment regimen.
      • Not a candidate for curative therapy or hematopoietic stem-cell transplantation (either due to disease burden, fitness, or preference).
      • Prior PD-1 or CTLA-4 targeted therapies are excluded.
    • Phase 2 expansion: TNBC

      • Histologically confirmed breast adenocarcinoma that is unresectable loco regional, or metastatic
      • Pathologically confirmed as triple negative, source documented, defined as both of the following:
      • Estrogen receptor (ER) and progesterone receptor (PgR) negative.
      • Human epidermal growth factor receptor 2 (HER2) negative as per American Society of Clinical Oncology/College of American Pathologists guidelines.
      • Subject must have received at least 1 prior systemic regimen for advanced or metastatic disease
      • Prior PD-1 or CTLA-4 targeted therapies are excluded.
    • Phase 2 expansion: RCC

      • Subjects with histological or cytological confirmation of clear cell RCC.
      • Not curable by surgery.
      • Subjects must have received prior antiangiogenic therapy.
      • Subjects must not have received prior immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy.
    • Phase 2 expansion: MSI high CRC

      • Subjects with histological confirmation of locally advanced unresectable or metastatic MSI high CRC.
      • MSI status is, respectively, determined by examining CRC tumor.
      • Subjects may have received no more than 2 lines of prior therapy for advanced disease.
    • Phase 2 expansion: Gastric Cancer

      • Must have histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.
      • Must have progression on or after therapy containing platinum/fluoropyrimidine or refused standard therapy.
      • Subjects may have received no more than 2 lines of prior therapy for advanced disease.
      • Prior PD-1 or CTLA-4 targeted therapies are excluded.
    • Phase 2 expansion: HCC

      • Must have histologically or cytologically confirmed diagnosis of HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).
      • Barcelona Clinic Liver Cancer (BCLC) Stage C disease (Llovet et al 1999), or BCLC Stage B disease.
      • Subjects may have received no more than 2 lines of prior therapy for the advanced disease
      • Must have progressed on, refused, or were intolerant of sorafenib.
      • The following are excluded: Subjects with liver transplants, clear invasion of the bile duct or main portal branch(es), or hepatorenal syndrome, or subjects who have required esophageal variceal ablation within 28 days of starting study treatment.
      • Prior PD-1 or CTLA-4 targeted therapies are excluded.
    • Tumor biopsies are required. If a subject has inaccessible lesions, such as in ovarian cancer, HCC, or gastric cancer, or highly vascular lesions, such as RCC, enrollment may be considered with medical monitor approval, and archived tissue may be acceptable.
    • Females of child-bearing potential and males who use adequate birth control through 120 days post dose.

Exclusion Criteria:

  • Subjects who participated in any other study in which receipt of an investigational study drug or device occurred within 2 weeks or 5 half-lives (whichever is longer) prior to first dose.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Exception: Prior anti−CTLA-4 in the adjuvant setting for subjects with melanoma would be permitted.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable.
  • Has an active autoimmune disease.
  • Has evidence of noninfectious pneumonitis that required steroids or current pneumonitis.
  • Live vaccine use within 30 days of first dose of study medication.
  • Monoamine oxidase inhibitors.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02178722


Locations
Show Show 24 study locations
Sponsors and Collaborators
Incyte Corporation
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Mark Jones, MD Incyte Corporation
  Study Documents (Full-Text)

Documents provided by Incyte Corporation:
Study Protocol  [PDF] July 2, 2018
Statistical Analysis Plan  [PDF] May 17, 2019

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Responsible Party: Incyte Corporation
ClinicalTrials.gov Identifier: NCT02178722    
Other Study ID Numbers: INCB 24360-202/ ECHO-202
First Posted: July 1, 2014    Key Record Dates
Results First Posted: December 19, 2019
Last Update Posted: December 19, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Carcinoma, Renal Cell
Endometrial Neoplasms
Triple Negative Breast Neoplasms
Microsatellite Instability
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Adenocarcinoma
Liver Neoplasms
Liver Diseases
Urologic Neoplasms
Urologic Diseases
Kidney Neoplasms
Kidney Diseases
Uterine Neoplasms
Uterine Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases
Genomic Instability
Pathologic Processes
Pembrolizumab