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CBT-501 or Nivolumab in Combination With CBT-101 in Locally Advanced or Metastatic HCC and RCC

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ClinicalTrials.gov Identifier: NCT03655613
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : November 28, 2018
Sponsor:
Collaborator:
CBT Pharmaceuticals, Inc.
Information provided by (Responsible Party):
CBT Pharmaceuticals (Australia) Pty Ltd

Brief Summary:

Study Design and Investigational Plan:

This is an open-label Phase 1/2 study to assess the safety and tolerability of combination PD-1 inhibitor (CBT-501 or nivolumab) administered concomitantly with c-Met inhibitor (CBT-101), to determine the recommended Phase 2 dose of the combination, and to obtain preliminary efficacy in HCC or RCC subjects with advanced or metastatic disease that have not been previously treated with a PD 1 inhibitor or a c-Met inhibitor. HCC subjects will receive the combination CBT-501 plus CBT-101 while RCC subjects will receive the combination nivolumab plus CBT-101. In Phase 1, mandatory archival or fresh tumor biopsies will be collected. In Phase 2, a mandatory fresh tumor biopsy will be required for study entry and another fresh biopsy will be collected between Cycles 2 and 4. The frequency of administration of PD-1 inhibitors will be every 2 weeks starting in Cycle 1 on Day 8 and Day 22 of a 35-day cycle with all subsequent cycles on Day 1 and Day 15 of 28-day cycles. CBT 101 will be administered orally every 12 hours continuously on an empty stomach.


Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Renal Cell Carcinoma Biological: CBT-501 Drug: CBT-101 Biological: Nivolumab Phase 1 Phase 2

Detailed Description:
For each potential subject, there is a 28-day screening and eligibility assessment period before enrollment; the first dose of study treatment will be administered on Day 1 of Cycle 1 (C1D1) (Safety population). Subjects will continue to receive their assigned treatment throughout the study until the occurrence of confirmed disease progression [progressive disease (PD)] by irRECIST, death, unacceptable treatment-related toxicity, or until the study is closed by the Sponsor. During the treatment period, study visits will occur on Day 1, Day 2, Day 8, Day 15, Day 22 of Cycle 1 and Day 1 and Day 15 of every subsequent cycle. Subjects who experience a response [Complete Response (CR), Partial Response (PR)] ≥ 2 cycles, PD 1 plus CBT-101 combination will be continued until disease progression based on irRECIST. Subjects should receive a minimal of 2 cycles of PD-1 and CBT-101 for adequate evaluation of response (Evaluable population). Discontinuation of PD-1 and CBT-101 should occur upon determination of disease progression as determined by irRECIST, intolerable toxicity or when the risk/benefit ratio is no longer beneficial for the subjects as determined by the Principal Investigator, or upon subject withdrawal of consent. Upon permanent discontinuation of study treatment, there is a Treatment Termination visit and three monthly follow-up visits for a 90-day safety follow-up visit period. Subjects who drop out before they complete the first cycle of combination treatment for reasons other than toxicity will be replaced

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 119 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: (Phase 1) 3+3 dose escalation (Phase 2) Simon two-stage Minimax design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Dose Escalation and Expansion Study of Combination CBT-501 or Nivolumab With CBT-101 in Locally Advanced or Metastatic Hepatocellular and Renal Cell Carcinoma
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : September 15, 2020
Estimated Study Completion Date : December 15, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Arm A: Hepatocellular Carcinoma
PD-1 inhibitor (CBT-501) 3 mg/kg intravenously every 2 weeks + c-Met inhibitor (CBT-101) 300 mg or 400 mg administered twice daily continuously until documented disease progression, discontinuation due to toxicity withdrawal of consent or the study ends
Biological: CBT-501
Humanized IgG4 monoclonal antibody against programmed death receptor-1 (PD-1)
Other Name: genolimzumab

Drug: CBT-101
Oral specific c-Met inhibitor
Other Name: bozitinib

Experimental: Arm B: Renal Cell Carcinoma
PD-1 inhibitor (nivolumab) 3 mg/kg or 240 mg intravenously every 2 weeks + c-Met inhibitor (CBT-101) 300 mg or 400 mg administered twice daily continuously until documented disease progression, discontinuation due to toxicity withdrawal of consent or the study ends
Drug: CBT-101
Oral specific c-Met inhibitor
Other Name: bozitinib

Biological: Nivolumab
Fully human IgG4 monoclonal antibody against PD-1
Other Name: Opdivo




Primary Outcome Measures :
  1. Dose Limiting Toxicities (Phase 1) [ Time Frame: Cycle 1 (up to 35 days) ]
    Dose limiting toxicities (DLTs)


Secondary Outcome Measures :
  1. Adverse events [ Time Frame: First dose up to 90 days post last dose (up to approximately 2 years) ]
    Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0. including immune related adverse events (irAEs)

  2. Drug discontinuation due to adverse events [ Time Frame: First dose up to 90 days post last dose (up to approximately 2 years) ]
    Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0. including immune related adverse events (irAEs)

  3. Overall Response Rate [ Time Frame: Duration of study, performed at baseline, then every 8 weeks until objective disease progression (up to approximately 2 years) ]
    Tumor response will be assessed by immune related Response Evaluation Criteria in Solid Tumors (irRECIST)

  4. Time to Response [ Time Frame: Duration of study, first dose to first response (up to approximately 2 years) ]
    Time to response is the time from first dose to date of first response (Partial response or Complete response)

  5. Progression Free Survival [ Time Frame: Duration of study, performed at baseline, then every 8 weeks until objective disease progression at 6, 12, 18 and 24 months (up to approximately 2 years) ]
    Progression free survival will be collected on all enrolled subjects, defined as the time from first dose to death from any cause or first observed disease progression

  6. Overall Survival [ Time Frame: Duration of study, performed every 8 weeks from enrollment to death from any cause at 6, 12, 18, 24 months (up to approximately 2 years) ]
    Overall survival will be estimated using the Kaplan-Meier method with the follow-up starting at the initiation of therapy until date of death



Information from the National Library of Medicine

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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:

  1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent.
  2. Men and women 18 years of age or older.
  3. Histologically confirmed advanced or metastatic hepatocellular carcinoma that progressed while receiving at least one previous line of systemic therapy, including sorafenib, or who are intolerant of or refused sorafenib treatment following progression on standard therapy including surgical and/or local regional therapies, or standard therapy considered ineffective, intolerable, or inappropriate or for which no effective standard therapy is available.
  4. Histologically confirmed advanced or metastatic renal cell carcinoma with clear cell component who received one or two prior lines of antiangiogenic therapy in addition to no more than three previous regimens of systemic therapy including cytokines and cytotoxic chemotherapy agents.
  5. Disease according to irRECIST that can be reliably and consistently followed.
  6. Documented disease progression during or after the last treatment regimen and within 6 months before study enrollment.
  7. Tumor amenable to tumor biopsy and subject agreeable to tumor biopsy at study entry and during therapy with study treatment.
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  9. Acceptable organ function.

Exclusion Criteria:

  1. History of severe hypersensitivity to mAbs, excipients of the CBT-501, nivolumab, or CBT-101.
  2. History of receiving treatment with any c-Met signaling pathway inhibitor (marketed or investigational agents).
  3. Prior therapy with anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or any other antibody targeting T cell co-stimulation pathways).
  4. Unwilling to swallow orally administered medication whole.
  5. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., Crohn's, ulcerative colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
  6. Documented and/or known history of human immunodeficiency virus (HIV) for HCC and RCC subjects, or historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) (RCC only).
  7. HCC subjects receiving active antiviral therapy for HCV.
  8. Active co-infection with HBV and HCV.
  9. Active co-infection with HBV and hepatitis D virus.

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): NCT03655613


Contacts
Contact: Elizabeth Bergan 925.271.9535 elizabeth.bergan@cbtpharma.com
Contact: Gavin Choy, PharmD 925.272.4090 gavin.choy@cbtpharma.com

Locations
Australia, New South Whales
Crown Princess Mary Cancer Centre Recruiting
Westmead, New South Whales, Australia, 2145
Contact: Joanna Jackson    +61 (2) 8890 8377    joanna.jackson@sydney.edu.au   
Principal Investigator: Mark Y Wong, MD         
Australia, South Australia
Ashford Cancer Center Recruiting
Adelaide, South Australia, Australia, 5037
Contact: Helen Daykin    +61 (0)882922220    hdaykin@adelaidecancercentre.com.au   
Principal Investigator: Amy Hsieh         
Australia, Victoria
Royal Melbourne Hospital Recruiting
Melbourne, Victoria, Australia, 3050
Contact: Irene Bell    +61(0)393482004    irene.bell@mh.org.au   
Principal Investigator: Siddharth Sood, MD         
Australia, Western Australia
Fiona Stanley Hospital Recruiting
Murdoch, Western Australia, Australia, 6150
Contact: Caroline Stone    +61(8) 6152 6530    caroline.stone@health.wa.gov.au   
Contact: Muhammad A Khattak, MD         
Principal Investigator: Muhammad A Khattak, MD         
Afffinity Clinical Research Recruiting
Perth, Western Australia, Australia, 6018
Contact: Krystyne Hiscock    +61 (0)8 9446 8726    pm1@affinityresearch.com.au   
Principal Investigator: Alex Powell, MD         
New Zealand
Auckland City Hospital Recruiting
Auckland, New Zealand, 1023
Contact: Sarah Coates    +64 9529 4001    scoates@adhb.govt.nz   
Contact: Bibin George    +64 9529 4001    BibinG@adhb.govt.nz   
Principal Investigator: Edward Gane, MD         
Sponsors and Collaborators
CBT Pharmaceuticals (Australia) Pty Ltd
CBT Pharmaceuticals, Inc.
Investigators
Study Chair: Tillman Pearce, MD CBT Pharmaceuticals (Australia) Pty Ltd

Responsible Party: CBT Pharmaceuticals (Australia) Pty Ltd
ClinicalTrials.gov Identifier: NCT03655613     History of Changes
Other Study ID Numbers: APOLLO
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: November 28, 2018
Last Verified: November 2018

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

Keywords provided by CBT Pharmaceuticals (Australia) Pty Ltd:
Immunotherapy
PD-1 inhibitor
c-Met inhibitor

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs