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Phase 1 Multicenter Study of the Safety, Pharmacokinetics, and Preliminary Efficacy of CBT-101 in Subjects With Advanced Solid Tumors and c-Met Dysregulation

Description

This is a Phase 1, multi-center, open-label, 2-part study with a Dose Escalation Segment and Dose and Disease Expansion Cohorts study of CBT-101, a c-MET inhibitor, to determine the recommended Phase 2 dose (RP2D) and dose limiting toxicities for CBT-101, and to obtain preliminary efficacy and target engagement data, in subjects with advanced malignancies and c-Met dysregulation. c-MET dysregulation will be determined from historical results by molecular pre-screening evaluations to determine eligibility of enrollment for both the Dose Escalation Segment and Dose and Disease Expansion Cohorts. However, in the Dose and Disease Expansion Cohorts, the c-MET historical results will be confirmed by a central laboratory retrospectively, but will not be a determinant for study entry. Dose escalation will occur in three subject cohorts until a protocol defined dose limited toxicity (DLT) occurs and a tentative maximum tolerated dose (MTD) is determined. At the tentative MTD or RP2D, at least 16 additional subjects for each stated tumor type (renal cell carcinoma, advanced gastric carcinoma (including gastroesophageal junction adenocarcinoma), and a biomarker driven basket of tumors with c-MET dysregulation will be assessed to further evaluate toxicity and preliminary efficacy.

Phase

N/A

Inclusion and Exclusion Criteria

  • Able to understand and comply with study procedures, understand the risks involved, and provide written informed consent.
  • Dose Escalation Segment: histologically and / or cytological confirmed locally advanced, recurrent or relapsed, or metastatic incurable solid malignancy with no limit on the number of prior lines of standard therapy.
  • Dose and Disease Expansion Cohorts: histologically confirmed renal cell carcinoma, gastric carcinoma (including gastro-esophageal junction adenocarcinoma), and a biomarker driven cohort of tumors with evidence of c-MET dysregulation (amplification, mutation)
  • Renal Cell Carcinoma: documented histological or cytological diagnosis of renal cell cancer with a clearcell or papillary component; progression following at least two prior lines of standard therapy including a checkpoint inhibitor and an anti-VEGFR inhibitor; archival tissue or fresh tumor biopsy
  • Gastric Carcinoma (including Gastro-Esophageal Junction Adenocarcinoma): progression following at least one prior line of standard therapy that contained a fluoropyrimidine and/or platinum and/or taxane agent; prior adjuvant or neoadjuvant therapy is counted as one regimen, provided that disease progression occurs within 6 months after the completion of adjuvant or neoadjuvant therapy; HER2 negative subjects (defined by HER2 ≤ 2+ by IHC) by medical history; archival tissue or fresh tumor biopsy
  • Abnormal c-MET dysregulation, defined as the following from archival historical results of molecular pre-screening evaluations.
  • Dose Escalation Segment
  • c-MET overexpression, ≥ 50% tumor cells with immunohistochemistry Grade 3+
  • or c-MET amplification; FISH c-MET to chromosome 7 (CEP 7) ratio ≥ 2.2; NGS copy number variation ≥ 4
  • or mutation, including any deletions and any met fusions
  • Dose and Disease Expansion Cohorts
  • c-MET amplification; FISH c-MET to chromosome 7 (CEP 7) ratio ≥ 2.2; NGS copy number variation ≥ 4
  • or mutation, including any deletions and any met fusions
  • Measurable disease according to RECIST v1.1
  • No chemotherapy treatments within at least 3 weeks prior to first dose of study treatment. For all prior anticancer treatment, including radiotherapy or targeted agents or hormonal therapy, a duration of more than 5 half-lives of the targeted/hormonal agents used must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria.
  • Adequate cardiac function (≤ NYHA Class II) or normal cardiac function with left ventricular ejection fraction (LVEF) ≥ 50% at screening. Major

  • Hypersensitivity to CBT-101, excipients of the drug product, or other components of the study treatment regimen.
  • History of receiving treatment with any c-MET signaling pathway inhibitor (marketed or investigational agents)
  • History of, or at risk for, cardiac disease (e.g., long QT syndrome [> 450 msec] or concurrent treatment with any medication that prolongs QT interval).
  • Symptomatic primary tumors or metastasis of brain and/or central nervous system, uncontrolled with antiepileptic and requiring high doses of steroids.
  • Unable to swallow orally administered medication whole.
  • 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).
  • Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks before randomization. Subjects with complications from prior radiation therapy are not eligible and AEs must return to baseline or ≤ Grade 1.

Sites

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