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

NCT02825836 | Unknown Phase 1 FDA Drug

• 2 other identifiers: MS200662_00012016-000286-23
• Study Type: interventional
• Target: 130
• Locations: 7 countries
• Sites: 17

Brief Summary

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.

Conditions

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

Keywords

TL-895; Tyrosine Kinase Inhibitor; Lymphoma; Open; Phase I; Phase II; CLL; SLL

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Part 1 (Dose Escalation): Best Overall Response (BOR)/Progression Free Survival (PFS)

  Baseline up to 6 months on treatment

• Part 2 (Dose Expansion): Overall CR/CRi rate

  Baseline up to end of study (2 years after last patient enrolled)

• Part 2: Duration of Clinical Response (DOR)

  Baseline up to end of study (2 years after last patient enrolled)

• Part 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)

  Baseline up to end of study (2 years after last patient enrolled)

• Part 2: Assessment of Safety and Tolerability via Clinical Measurements

  Baseline up to end of study (2 years after last patient enrolled)

Study Arms (12)

TL-895 80/160 mg QD in R/R Participants

EXPERIMENTAL

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

TL-895 300 mg QD in R/R Participants

EXPERIMENTAL

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

TL-895 600 mg QD in R/R Participants

EXPERIMENTAL

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

TL-895 300 mg BID in R/R Participants

EXPERIMENTAL

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

TL-895 900 mg QD in R/R Participants

EXPERIMENTAL

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

TL-895 100 mg BID in R/R Participants

EXPERIMENTAL

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

TL-895 150 mg BID in R/R Participants

EXPERIMENTAL

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

TL-895 150 mg BID in Treatment Naïve Participants

EXPERIMENTAL

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

TL-895 100 mg BID in Treatment Naïve Participants

EXPERIMENTAL

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

TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants without 17p(del)

EXPERIMENTAL

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; Drug: Navtemadlin

TL-895 150 mg BID & navtemadlin 240mg QD in Treatment Naïve Participants without 17p(del)

EXPERIMENTAL

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; Drug: Navtemadlin

TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants with 17p(del)

EXPERIMENTAL

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; Drug: Navtemadlin

Interventions

TL-895 DRUG

TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.

TL-895 100 mg BID in R/R Participants; TL-895 100 mg BID in Treatment Naïve Participants; TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants with 17p(del); TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants without 17p(del); TL-895 150 mg BID & navtemadlin 240mg QD in Treatment Naïve Participants without 17p(del); TL-895 150 mg BID in R/R Participants; TL-895 150 mg BID in Treatment Naïve Participants; TL-895 300 mg BID in R/R Participants; TL-895 300 mg QD in R/R Participants; TL-895 600 mg QD in R/R Participants; TL-895 80/160 mg QD in R/R Participants; TL-895 900 mg QD in R/R Participants

Navtemadlin DRUG

Navtemadlin is an experimental MDM2 anticancer drug taken by mouth.

TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants with 17p(del); TL-895 150 mg BID & navtemadlin 240mg QD in R/R Participants without 17p(del); TL-895 150 mg BID & navtemadlin 240mg QD in Treatment Naïve Participants without 17p(del)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Prior treatment with any BTK or PI3K inhibitors
• History of major organ transplant
• Women who are pregnant or breastfeeding

Sponsors & Collaborators

• Telios Pharma, Inc.: lead

Study Sites (17)

Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

The West Clinic

Germantown, Tennessee, 38138, United States

Location

Debreceni Egyetem - Borgyógyászati Klinika

Debrecen, 4002, Hungary

Location

Eger Markhot Ferenc Kórház

Eger, 3300, Hungary

Location

Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi - Istituto di Ematologia e Oncologia Medica

Bologna, 40138, Italy

Location

Examen sp. z o. o.

Skorzewo, Poznań, 60-185, Poland

Location

Pratia MCM Krakow

Krakow, 30-510, Poland

Location

Centrum Onkologii Ziemi Lubelskiej im sw Jana z Dukli Oddzial Hematologiczny

Lublin, 20-090, Poland

Location

Szpital Wojewódzki

Opole, 46-020, Poland

Location

Nasz Lekarz Przychodnie Medyczne

Torun, 87-100, Poland

Location

Saint Petersburg State Medical University

Saint Petersburg, 197022, Russia

Location

Yaroslavl Regional Clinical Hospital

Yaroslavl, 150023, Russia

Location

Communal Non-profit Enterprise Regional Center of Oncology

Kharkiv, 61000, Ukraine

Location

Kyiv City Clinical Hospital #4

Kyiv, 03110, Ukraine

Location

Mykolaiv Regional Clinical Hospital

Mykolaiv, 54058, Ukraine

Location

University College London Hospitals - NIHR/Wellcome Trust

London, United Kingdom

Location

Derriford Hospital - Dept of Haematology

Plymouth, United Kingdom

Location

Related Publications (4)

• Eugenio Gaudio, Chiara Tarantelli, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni. The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2017-4182

  BACKGROUND

• Goodstal SM, Lin J, Crandall T, Crowley L, Bender AT, Pereira A, Soloviev M, Wesolowski JS, Iadevaia R, Schelhorn SE, Ross E, Morandi F, Ma J, Clark A. Preclinical evidence for the effective use of TL-895, a highly selective and potent second-generation BTK inhibitor, for the treatment of B-cell malignancies. Sci Rep. 2023 Nov 21;13(1):20412. doi: 10.1038/s41598-023-47735-z.

  PMID: 37989777 BACKGROUND

• Wojciech Jurczak, Simon Rule, William Townsend, David Tucker, Martin Dyroff, Barbara Sarholz, Jürgen Scheele, John G. Gribben and Pier Luigi Zinzani. First in Human, Phase I/II Trial of the Bruton's Tyrosine Kinase Inhibitor (BTKi) M7583 in Patients with B Cell Malignancies: Study Design and Initial Outcomes. Blood 2017 130:2778.

  BACKGROUND

• Jurczak W, Rule S, Townsend W, Tucker D, Sarholz B, Scheele J, Dyroff M, Gribben JG, Dlugosz-Danecka M, Zinzani PL. Phase I, first-in-human trial of Bruton's tyrosine kinase inhibitor M7583 in patients with B-cell malignancies. Leuk Lymphoma. 2021 Oct;62(10):2392-2399. doi: 10.1080/10428194.2021.1913139. Epub 2021 Apr 24.

  PMID: 33896333 BACKGROUND

MeSH Terms

Conditions

Recurrence; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma

Interventions

navtemadlin; 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2016
• First Posted: July 7, 2016
• Study Start: August 26, 2016
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2025
• Last Updated: July 13, 2023

Record last verified: 2023-07

Locations

GB (2); HU (2); IT (1); UA (3); US (2); PL (5); RU (2)