Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects

Study Overview
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Brief Summary
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The purpose of this research study is to determine the safety and tolerability of TL-895. There are 2 parts of this study. Part 1 tested increasing doses of TL-895 to identify the recommended safe dose for participants with relapsed/refractory (R/R) B cell malignancies who failed at least 1 but no more than 3 prior therapies. Part 1 of this study is no longer enrolling participants. Arms 1 & 2 of Part 2 of this study will test different doses of TL-895 in participants with R/R CLL or SLL who have failed at least 1 prior therapy. Arms 1 & 2 of Part 2 of this study is randomized (like the flip of a coin) to receive a specific treatment dose. If someone participates in arms 1 or 2 of Part 2, the dose they receive will be either 100mg twice a day or 150mg twice a day. Arms 3 and 4 of Part 2 of this study will test the 150mg and 100mg BID dose of TL-895, respectively in treatment naïve participants with CLL/SLL. Arms 5 and 6 of Part 2 will test 150mg TL-895 BID in combination with 240 mg navtemadlin QD in participants with relapsed/refractory and treatment naïve without 17p(del). Arm 7 will test 150mg TL-895 in combination with 240 mg navtemadlin QD in participants with relapsed/refractory CLL/SLL with 17p(del). Every participant in this study will receive TL-895.

Official Title
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Phase I/II, First in Human, Dose Escalation Trial of TL 895 Monotherapy in Subjects With Relapsed/Refractory B Cell Malignancies and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Treatment-Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Subjects and Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Relapsed/Refractory Small Lymphocytic Lymphoma

Conditions
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Relapsed/Refractory B Cell Malignancies, Mantle Cell Lymphoma and Diffuse Large B Cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Treatment-Naive B Cell Malignancies

Intervention / Treatment
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* Drug: TL-895
* Drug: Navtemadlin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Relapsed/refractory CLL or relapsed/refractory SLL (Arms 1, 2, 5, and 7) Treatment naïve CLL or SLL (Arm 3, 4, and 6) ECOG performance status of ≤ 2 Adequate hematologic, hepatic, and renal functions Exclusion Criteria Prior treatment with any BTK or PI3K inhibitors History of major organ transplant Women who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TL-895 80/160 mg QD in R/R Participants<br>Participants received TL-895 80 mg powder in capsule (PiC) orally once daily (OD) for 3 days followed by TL-895 160 mg OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 300 mg QD in R/R Participants<br>Participants received TL-895 300 mg PiC orally OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 600 mg QD in R/R Participants<br>Participants received TL-895 600 mg PiC orally OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 300 mg BID in R/R Participants<br>Participants received TL-895 300 mg PiC orally twice daily (BID) in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 900 mg QD in R/R Participants<br>Participants received TL-895 900 mg PiC orally QD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 100 mg BID in R/R Participants<br>Participants received TL-895 100 mg BID orally with food for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 150 mg BID in R/R Participants<br>Participants received TL-895 150 mg BID orally with food for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 150 mg BID in Treatment Naïve Participants<br>Participants received TL-895 150 mg BID orally with food for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 100 mg BID in Treatment Naïve Participants<br>Participants received TL-895 100 mg BID orally with food for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants without 17p(del)<br>Participants received navtemadlin 240 mg administered QD on Days 1-7 in combination with TL-895 150 mg BID orally with food for 28 days with in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Navtemadlin<br>* Navtemadlin is an experimental MDM2 anticancer drug taken by mouth.<br>|
| Experimental: TL-895 150 mg BID & navtemadlin 240mg QD in Treatment Naïve Participants without 17p(del)<br>Participants received navtemadlin 240 mg administered QD on Days 1-7 in combination with TL-895 150 mg BID orally with food for 28 days with in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Navtemadlin<br>* Navtemadlin is an experimental MDM2 anticancer drug taken by mouth.<br>|
| Experimental: TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants with 17p(del)<br>Participants received navtemadlin 240 mg administered QD on Days 1-7 in combination with TL-895 150 mg BID orally with food for 28 days with in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Navtemadlin<br>* Navtemadlin is an experimental MDM2 anticancer drug taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 (Dose Escalation): DLTs (Dose Limiting Toxicities) during Cycle 1 | DLT is defined as any of the adverse event (AEs) of a certain grade or above, related to drug. | Baseline up to the end of cycle 1 (28 days) | 
| Part 2 (Dose Expansion): Overall Response Rate (ORR) | The proportion of subjects achieving CR, CRi, nodular partial response (nPR), partial response (PR), or PR with lymphocytosis (PR-L) at any time while on the study based on iwCLL response criteria (2), as assessed by investigators | Baseline up to end of study (2 years after last patient enrolled) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 (Dose Escalation): Best Overall Response (BOR)/Progression Free Survival (PFS) | Defined by the length of time during the treatment of the disease, that a participant lives with the disease but it does not get worse based on investigator assessments | Baseline up to 6 months on treatment | 
| Part 2 (Dose Expansion): Overall CR/CRi rate | The proportion of subjects achieving CR/CRi based on iwCLL response criteria | Baseline up to end of study (2 years after last patient enrolled) | 
| Part 2: Duration of Clinical Response (DOR) | Time from initial response to disease progression or death from any cause | Baseline up to end of study (2 years after last patient enrolled) | 
| Part 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) | Incidence, nature, severity of treatment-emergent adverse events (TEAEs), and deaths, including cause of death, from screening up to the end of study visit of participants with CLL/SLL who have failed at least 1 line of therapy | Baseline up to end of study (2 years after last patient enrolled) | 
| Part 2: Assessment of Safety and Tolerability via Clinical Measurements | Assessments including but not limited to clinical laboratory measurements, ECGs, vital signs, and ECOG performance | Baseline up to end of study (2 years after last patient enrolled) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TL-895, Tyrosine Kinase Inhibitor, Lymphoma, Open, Phase I, Phase II, CLL, SLL