A Dose Escalation and Cohort Expansion Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors or Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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Part 1: Dose Escalation. The primary objective of Part 1 of this study is to evaluate the safety and tolerability of KB-0742 in participants with relapsed or refractory (R/R) solid tumors or non-Hodgkin lymphoma (NHL). Part 2: Cohort Expansion. The primary objective of Part 2 of this study is to further evaluate the safety and tolerability of KB-0742 in defined participant cohorts.

Official Title
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Phase 1, First-in-human, Open-label Dose Escalation and Cohort Expansion Study of KB-0742 in Patients With Relapsed or Refractory Solid Tumors or Non-Hodgkin Lymphoma

Conditions
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Relapsed Solid Tumors, Refractory Solid Tumors, Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: KB-0742


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥ 18 years old (Parts 1 and 2A); males or females ≥ 12 years old and with a body weight ≥ 40 kg are eligible to enroll with tumor types including soft-tissue sarcomas, Ewing's sarcoma, alveolar rhabdomyosarcoma, NUT midline carcinoma (NMC), or chordoma (Part 2B) Willing and able to provide consent (and assent for participants between the ages of 12 to <18) Part 1: Participants who meet at least 1 of the following criteria: Any relapsed/refractory (R/R) solid tumor with readily accessible biopsy sites and consenting to 1 baseline and 1 on-treatment biopsy if deemed feasible to perform. Tumor type of interest (see list below) with measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) or Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST) 1.0 for solid tumors or by Lugano Classification or Modified Weighted Assessment Tool (mSWAT) for non-Hodgkin lymphoma AND at least 1 measurable scan per one of the above criteria prior to the most recent scan to document the rate of tumor growth before the initiation of study treatment. Tumor types of interest (R/R without other available therapeutic options) are: Small cell lung cancer (SCLC) Epithelial ovarian cancer, triple negative breast cancer (TNBC), or non-small cell lung cancer (NSCLC) Diffuse large B-cell lymphoma with documented MYC translocation or Burkitt's lymphoma (as determined by local testing) Sarcoma with documented transcription factor fusion (as determined by local testing) Chordoma, NUT midline carcinoma, or adenoid cystic carcinoma Part 2, Cohort A: Participants with histologically or cytologically confirmed solid tumors who have failed, are intolerant to or are considered ineligible for standard-of-care anti-cancer treatments. Note: Part 2, Cohort A, will include participants with relapsed or refractory solid tumors including approximately 10 participants each with NSCLC, triple-negative breast cancer and ovarian cancer (MYC-dependent tumor types). • Part 2, Cohort B: Participants with histologically or cytologically confirmed SCLC or soft-tissue sarcomas with defined transcription factor oncogenic drivers as determined locally, including (but not limited to) chordomas, Ewing's sarcoma or alveolar rhabdomyosarcoma as well as NUT midline carcinomas (NMC) or adenoid cystic carcinomas, without access to or intolerant of other approved therapies. For both Parts 1 and 2: Access to a tumor sample for central laboratory testing Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 Evaluable or measurable disease, per RECIST 1.1 or PERCIST 1.0 for solid tumors or the Lugano Classification or mSWAT for non-Hodgkin lymphoma Adequate bone marrow and organ function Recovery from treatment-related toxicities from prior therapies to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≤ 1 or to baseline level Must agree to use highly effective birth control during the trial and for at least 3 months after the last dose of study drug; female participants cannot be pregnant or breastfeeding Exclusion Criteria: Any other anti-cancer therapies including chemotherapy, immunotherapy, or hormonal therapy within 4 weeks or 5 half-lives (whichever is shorter) History of surgery (except for diagnostic purposes) or non-palliative radiotherapy within 4 weeks History of allogeneic transplantation within 6 months Active central nervous system (CNS) involvement by the underlying malignancy; previously treated CNS metastatic disease is permitted with magnetic resonance imaging (MRI) documentation of stable disease for at least 3 months prior to study start History of stroke or intracranial hemorrhage within ≤6 months History of seizure disorder, ie, recurrent seizures with an underlying etiology and requiring ongoing anti-epileptic medication Current use of medications associated with seizure risk unless approved by Medical Monitor Active infections requiring systemic antibiotic, antiviral or antifungal therapy Known active coronavirus disease 2019 (COVID-19) Clinically significant heart disease Uncontrolled hypertension Prolongation of QT interval at baseline Known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>Sequential cohorts of participants will receive escalating doses of KB-0742. | Drug: KB-0742<br>* Oral capsules<br>|
| Experimental: Part 2: Cohort Expansion<br>Following identification of the recommended Phase 2 dose (RP2D) in Part 1, the following expansion cohorts will be enrolled: Cohort A: Relapsed or refractory (R/R) non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and ovarian cancer with evidence of MYC amplication/overexpression. Cohort B: Relapsed or refractory (R/R) small cell lung cancer (SCLC), NUT midline carcinomas (NMC), adenoid cystic carcinoma (ACC), chordoma and soft tissue sarcomas with evidence of transcription factor dysregulation. | Drug: KB-0742<br>* Oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Incidence of Adverse Events (AEs) | Type, incidence, severity, causality and outcome of adverse events (AEs), including serious AEs and AEs at Grade 3 or above, based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. | Cycle 1 Day 1 up to 30 days after the last dose, where each cycle is up to 28 days (up to approximately 38 months) | 
| Part 1 and Part 2: Number of Participants with Dose Limiting Toxicity (DLT) of KB-0742 |  | Cycle 1 Day 1 through Cycle 2 Day 1, where each cycle is up to 28 days | 
| Part 1: Maximally Tolerated Dose (MTD) of KB-0742 |  | Cycle 1 Day 1 through Cycle 2 Day 1, where each cycle is up to 28 days | 
| Part 1: Recommended Phase 2 Dose (RP2D) of KB-0742 |  | Cycle 1 Day 1 through Cycle 2 Day 1, where each cycle is up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximal Plasma Concentration (Cmax) of KB-0742 |  | Cycle 1 Day 1 through Cycle 2 Day 1, where a cycle is up to 28 days | 
| Part 2: Maximal Plasma Concentration (Cmax) of KB-0742 |  | Cycle 1 Day 1 and Cycle 1 Day 10, where a cycle is up to 28 days | 
| Part 1: Time to Maximal Plasma Concentration (Tmax) of KB-0742 |  | Cycle 1 Day 1 through Cycle 2 Day 1, where a cycle is up to 28 days | 
| Part 2: Time to Maximal Plasma Concentration (Tmax) of KB-0742 |  | Cycle 1 Day 1 and Cycle 1 Day 10, where a cycle is up to 28 days | 
| Part 1: Area Under The Plasma Concentration x Time Curve From Hour 0 to The Last Measurable Time Point (AUC0-last) of KB-0742 |  | Cycle 1 Day 1 through Cycle 2 Day 1, where a cycle is up to 28 days | 
| Part 2: Trough Concentration (Ctrough) of KB-0742 |  | Cycle 1 Day 1 and Cycle 1 Day 10, where a cycle is up to 28 days | 
| Part 1 and Part 2: Progression Free Survival (PFS) |  | Cycle 1 Day 1 up to 30 days after the last dose, where each cycle is up to 28 days (up to approximately 38 months) | 
| Part 1 and Part 2: Disease Control Rate |  | Cycle 1 Day 1 up to 30 days after the last dose, where each cycle is up to 28 days (up to approximately 38 months) | 
| Part 1 and Part 2: Duration of Disease Control |  | Cycle 1 Day 1 up to 30 days after the last dose, where each cycle is up to 28 days (up to approximately 38 months) | 
| Part 1 and Part 2: Overall Response Rate (ORR) |  | Cycle 1 Day 1 up to 30 days after the last dose, where each cycle is up to 28 days (up to approximately 38 months) | 
| Part 1 and Part 2: Duration of Response (DOR) |  | Cycle 1 Day 1 up to 30 days after the last dose, where each cycle is up to 28 days (up to approximately 38 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KB-0742, Relapsed Solid Tumors, Refractory Solid Tumors, Non-Hodgkin Lymphoma, CDK9 Inhibitor