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Navtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03787602
Recruitment Status : Recruiting
First Posted : December 26, 2018
Last Update Posted : March 2, 2023
Sponsor:
Information provided by (Responsible Party):
Kartos Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE December 6, 2018
First Posted Date  ICMJE December 26, 2018
Last Update Posted Date March 2, 2023
Actual Study Start Date  ICMJE March 19, 2019
Estimated Primary Completion Date November 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2022)
  • Cohort 1 Part 1: To determine the KRT-232 RP2D. [ Time Frame: 10 Weeks ]
    The Safety Review Committee (SRC) will determine RP2D for expansion based on safety and tolerability of each arm.
  • Cohort 1 Part 2: To determine the objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria version 1.1 after all subjects have been treated at the RP2D of KRT 232 and completed the second response assessment.
  • Cohort 2 Part 1: To determine the KRT-232 RP2D in combination with avelumab [ Time Frame: 28 Days ]
    DLTs will be used to establish the MTD of KRT-232 in combination with avelumab. SRC will determine the RP2D based on the safety of combination of KRT-232 with avelumab.
  • Cohort 2 Part 2: To determine the objective response rate (ORR) in treatment-naïve subjects with p53WT MCC [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria version 1.1 after all 30 subjects have been treated at the RP2D of in combination with avelumab and have completed the second response assessment.
  • Cohort 3: To determine the confirmed overall response rate (ORR) based on IRC assessments in subjects with p53WT MCC are chemotherapy naive and have failed anti-PD-1/PD-L. [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria 1.1 by IRC.
  • Cohort 4: To determine the confirmed overall response rate (ORR) based on IRC assessments in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy and have had least 1 line of prior chemotherapy. [ Time Frame: 10 Weeks ]
    ORR will be assessed per RECIST criteria 1.1 by IRC.
Original Primary Outcome Measures  ICMJE
 (submitted: December 21, 2018)		 To determine the objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy [ Time Frame: 42 days ]
The proportion of patients achieving a CR or PR as determined by RECIST 1.1 after 2 cycles of treatment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2022)
  • To determine the confirmed ORR based on investigator assessment. [ Time Frame: 1 year after last subject enrolled. ]
    ORR will be assessed per RECIST criteria 1.1 by investigators.
  • To determine the duration of response (DoR) [ Time Frame: 1 year after last subject enrolled ]
    Time from documentation of response (CR or PR as determined by RECIST 1.1) until disease progression.
  • To determine Progression-free survival (PFS) [ Time Frame: 1 year after last subject enrolled ]
    Time from initial treatment until disease progression.
  • To determine overall survival (OS) [ Time Frame: 1 year after last subject enrolled ]
    Time from initial treatment until death from any cause.
  • To determine clinical benefit rate (CBR) [ Time Frame: 1 year after last subject enrolled. ]
    PR, CR or stable disease that last at least 10 weeks, per IRC or investigator assessment.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2018)
  • To determine the duration of response (DoR) [ Time Frame: 1 year after last subject enrolled ]
    Time from documentation of response (CR or PR as determined by RECIST 1.1) until disease progression
  • To determine Progression-free survival (PFS) [ Time Frame: 1 year after last subject enrolled ]
    Time from initial treatment until disease progression
  • To determine overall survival (OS) [ Time Frame: 1 year after last subject enrolled ]
    Time from initial treatment until death from any cause
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Navtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma
Official Title  ICMJE A Phase 1b/2, Open-Label Study Evaluating the Safety and Efficacy of KRT-232 in Patients With p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC) Who Have Failed Anti-PD-1 or Anti-PD-L1 Immunotherapy, or in Combination With Avelumab in MCC Patients Who Are Anti-PD-1 or Anti-PD-L1 Treatment Naïve
Brief Summary This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with Merkel Cell Carcinoma (MCC) who have failed treatment with at least one anti-PD-1 or anti-PD-L1 immunotherapy or in combination with avelumab in MCC patients who are anti-PD-1 or anti-PD-L1 treatment naïve. Inhibition of MDM2 is a novel mechanism of action in MCC.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Merkel Cell Carcinoma
Intervention  ICMJE
  • Drug: KRT-232
    KRT-232 is an experimental MDM2 anticancer drug taken by mouth.
    Other Name: navtemadlin
  • Drug: Avelumab
    Avelumab is a PD-L1 blocking antibody anticancer drug administered by intravenous infusion.
    Other Name: Bavencio
Study Arms  ICMJE
  • Experimental: Cohort 1, Arm 1
    KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 1, Arm 1b
    KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 1, Arm 2b
    KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 1, Arm 3
    KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 1, Arm 5
    KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 1 Expansion
    KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 2, Arm 1 KRT-232 in combination with avelumab
    KRT-232 will be administered orally, once daily (QD) on Days 1-5, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.
    Interventions:
    • Drug: KRT-232
    • Drug: Avelumab
  • Experimental: Cohort 2, Arm 2 KRT-232 in combination with avelumab
    KRT-232 will be administered orally, once daily (QD) on Days 1-7, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.
    Interventions:
    • Drug: KRT-232
    • Drug: Avelumab
  • Experimental: Cohort 2 Expansion
    KRT-232 will be administered orally, once daily (QD) per RP2D dose and schedule, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.
    Interventions:
    • Drug: KRT-232
    • Drug: Avelumab
  • Experimental: Cohort 3
    KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
    Intervention: Drug: KRT-232
  • Experimental: Cohort 4
    KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
    Intervention: Drug: KRT-232
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2022)		 115
Original Estimated Enrollment  ICMJE
 (submitted: December 21, 2018)		 27
Estimated Study Completion Date  ICMJE August 2025
Estimated Primary Completion Date November 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • For Cohort 1, 3 and 4 patients must have failed treatment with at least one PD-1 inhibitor or PD-L1 inhibitor for metastatic MCC
  • For Cohort 2, patients must not have received any anti-PD-1 or anti-PD-L1 therapy
  • For Cohort 3, patients must not have received any prior chemotherapy
  • For Cohort 4, patients must have received at least one prior line of chemotherapy
  • ECOG performance status of 0 to 1
  • Histologically confirmed MCC. Disease must be measurable, with at least 1 measurable lesion by RECIST 1.1
  • MCC expressing p53WT based on any CLIA or test approved by local health authority or a validated test (Cohort 1 and 2)
  • MCC expressing p53WT based Central Lab test (Cohort 3 and 4)
  • Adequate hematological, hepatic, and renal functions

Exclusion Criteria:

  • For Cohort 2, subjects must not have autoimmune disease, medical conditions requiring systemic immunosuppression, prior stem cell transplant, or active infection with HBV or HCV.
  • Patients previously treated with MDM2 antagonist therapies or p53-directed therapies
  • History of major organ transplant
  • Patients with known central nervous system (CNS) metastases that are previously untreated
  • Grade 2 or higher QTc prolongation (>480 milli-seconds per NCI-CTCAE criteria, version 5.0)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John Mei 650-542-0136 jmei@kartosthera.com
Contact: Emily Houlihan 401-954-8042 ehoulihan@kartosthera.com
Listed Location Countries  ICMJE Australia,   Brazil,   Canada,   France,   Germany,   Italy,   Korea, Republic of,   Netherlands,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03787602
Other Study ID Numbers  ICMJE KRT-232-103
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Kartos Therapeutics, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Kartos Therapeutics, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Kartos Therapeutics, Inc.
Verification Date February 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP