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Phase I/II, First in Human, Dose Escalation Trial of TL 895 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Relapsed/Refractory Small Lymphocytic Lymphoma

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ClinicalTrials.gov Identifier: NCT02825836
Recruitment Status : Recruiting
First Posted : July 7, 2016
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
Telios Pharma, Inc.

Tracking Information
First Submitted Date  ICMJE June 1, 2016
First Posted Date  ICMJE July 7, 2016
Last Update Posted Date September 16, 2021
Actual Study Start Date  ICMJE August 26, 2016
Estimated Primary Completion Date February 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2021)
  • Part 1 (Dose Escalation): DLTs (Dose Limiting Toxicities) during Cycle 1 [ Time Frame: Baseline up to the end of cycle 1 (28 days) ]
    DLT is defined as any of the adverse event (AEs) of a certain grade or above, related to drug.
  • Part 2 (Dose Expansion): Overall Response Rate (ORR) [ Time Frame: Baseline up to end of study (2 years after last patient enrolled) ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: July 1, 2016)
  • Part 1 (does escalation): Number of Subjects With at Least One Dose Limiting Toxicity (DLT) During Cycle 1 [ Time Frame: Baseline up to 28 Days (Cycle 1) ]
    DLT is defined as any of the adverse event (AEs) related to drug .Any drug related Grade 4 liver enzyme elevation; Any Grade >= 3 non-hematological AE related to drug excluding. Diarrhea of < 3 days duration following adequate & optimal therapy; Any asymptomatic Grade 3 increase in liver function tests resolving to base level in 7 days. Grade 3 skin toxicity resolving to Grade 2/ less in 7 days; Nausea & vomiting of < 3 days duration with therapy; Grade 3 hyperglycemia in patients with diabetes mellitus/decreased glucose tolerance which resolves in < 5 days with treatment; Fatigue /headache of < 7 days duration following initiation of supportive care; laboratory values out of the normal range with no clinical correlate & resolve to <=Grade 2 in 5 days with medical management; Any Grade 4 neutropenia of > 5 days duration, Grade >= 3 febrile neutropenia/Grade 4 hemoglobin decrease; Any Grade 4 thrombocytopenia/ Grade 3 thrombocytopenia with bleeding related to drug.
  • Part 2 (dose expansion): Best Overall Response (BOR) [ Time Frame: Baseline up to 6 months ]
    Best overall response would be assessed according to the revised International Working Group Criteria for non-Hodgkin's lymphoma and International workshop on CLL as assessed by Investigators.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2021)
  • Part 1 (Dose Escalation): Best Overall Response (BOR)/Progression Free Survival (PFS) [ Time Frame: Baseline up to 6 months on treatment ]
    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
  • Part 2 (Dose Expansion): Overall CR/CRi rate [ Time Frame: Baseline up to end of study (2 years after last patient enrolled) ]
    The proportion of subjects achieving CR/CRi based on iwCLL response criteria
  • Part 2: Duration of Clinical Response (DOR) [ Time Frame: Baseline up to end of study (2 years after last patient enrolled) ]
    Time from initial response to disease progression or death from any cause
  • Part 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to end of study (2 years after last patient enrolled) ]
    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
  • Part 2: Assessment of Safety and Tolerability via Clinical Measurements [ Time Frame: Baseline up to end of study (2 years after last patient enrolled) ]
    Assessments including but not limited to clinical laboratory measurements, ECGs, vital signs, and ECOG performance
Original Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2016)
  • Part 1: Best overall response [ Time Frame: Months 3 and 6 ]
    Best overall response would be assessed according to the revised International Working Group Criteria for non-Hodgkin's lymphoma and International workshop on CLL as assessed by Investigators.
  • Duration of response [ Time Frame: Months 3 and 6 ]
    Duration of response defined as time from first response (complete response (CR) or partial response (PR) whichever is first recorded) to progressive disease based on the Investigator assessment or death from any cause within 30 days of last tumor assessment. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions
  • Progression- free survival time [ Time Frame: Months 3 and 6 ]
    Progression free survival time defined as time from the first dose of trial treatment to progressive disease based on the Investigator assessment or death from any cause within 30 days of last tumor assessment.
  • Number of subjects With Adverse Events (AEs), Serious AEs, AEs Leading to Death and AEs Leading to Discontinuation [ Time Frame: Screening (Day -21 to -1) up to 3 years ]
    An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
  • Number of subjects with abnormalities in laboratory measurements, electrocardiogram (ECG)s, vital signs, and ECOG performance status [ Time Frame: Screening (Day -21 to -1) up to 3 years ]
  • Bruton's tyrosine kinase (BTK)occupancy in Peripheral blood mononuclear cell (PBMCs ) [ Time Frame: Screening (Day -21 to -1), Pre-dose , 2 hours post dose on Day 1, 15 ; post dose on Day 22 ]
  • Area under the plasma concentration-time curve from time zero to 8 hours after administration (AUC0 8h) [ Time Frame: Predose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
  • Maximum observed plasma concentration (Cmax) [ Time Frame: Predose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
  • Time to reach maximum plasma concentration (tmax), [ Time Frame: Predose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
  • Dose normalized Area under the Curve from time 0 to 8 hours(AUC0-8h) [ Time Frame: Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
    Dose normalized AUC 0-8 hours is calculated as the AUC0-8 divided by dose of the drug.
  • Dose normalized Cmax (Cmax/dose) [ Time Frame: Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
  • Accumulation ratio for Area under the curve AUC0-8h [Racc(AUC0-8h)] [ Time Frame: Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
    Accumulation ratio for AUC is calculated as AUC0-8h on cycle1 Day 15 divided by AUC0-8h, on cycle 1 Day 1.
  • Accumulation ratio for maximum plasma concentration Cmax [Racc(Cmax)] [ Time Frame: Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22 ]
    Accumulation ratio for Cmax is calculated as Cmax on cycle1 Day 15 divided by Cmax on cycle 1 Day 1.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I/II, First in Human, Dose Escalation Trial of TL 895 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Relapsed/Refractory Small Lymphocytic Lymphoma
Official Title  ICMJE Phase I/II, First in Human, Dose Escalation Trial of TL 895 in Subjects With Relapsed/Refractory B-Cell Malignancies and Expansion in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Relapsed/Refractory Small Lymphocytic Lymphoma
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.

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. Part 2 of this study is randomized (like the flip of a coin) to receive a specific treatment dose. If someone participates in Part 2, the dose they receive will be either 100mg twice a day or 150mg twice a day. Every participant in this study will receive TL-895.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Relapsed/Refractory B Cell Malignancies
  • Mantle Cell Lymphoma and Diffuse Large B Cell Lymphoma
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Intervention  ICMJE Drug: TL-895
All participants will receive TL-895 at the dose assigned at enrollment until disease progression, withdrawal of consent, or discontinuation from the study.
Study Arms  ICMJE
  • Experimental: TL-895 80/160 mg QD
    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.
    Intervention: Drug: TL-895
  • Experimental: TL-895 300 mg QD
    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.
    Intervention: Drug: TL-895
  • Experimental: TL-895 600 mg QD
    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.
    Intervention: Drug: TL-895
  • Experimental: TL-895 300 mg BID
    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.
    Intervention: Drug: TL-895
  • Experimental: TL-895 900 mg QD
    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.
    Intervention: Drug: TL-895
  • Experimental: TL-895 100 mg BID
    Participants received TL-895 100 mg BID orally BID with food for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.
    Intervention: Drug: TL-895
  • Experimental: TL-895 150 mg BID
    Participants received TL-895 150 mg BID orally BID with food for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.
    Intervention: Drug: TL-895
Publications *
  • 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
  • Samantha M. Goodstal, Jianguo Ma, Jing Lin, Timothy Crandall, Lindsey Crowley, Andrew Bender, Riham Iadevaia and Anderson Clark. M7583 Is a Highly Selective and Potent Second Generation BTK Inhibitor for Treatment of B-Cell Malignancies. Blood 2017 130:3845.
  • 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.
  • Simon Rule, David Tucker, Anup Kalapur, Barbara Sarholz, Jürgen Scheele, Pier Luigi Zinzani. Phase I/II, first in human trial of the Bruton's tyrosine kinase inhibitor (BTKi) M7583 in patients with B cell malignancies. J Clin Oncol 35, 2017 (suppl; abstr e14101).

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 2, 2020)
58
Original Estimated Enrollment  ICMJE
 (submitted: July 1, 2016)
60
Estimated Study Completion Date  ICMJE February 1, 2024
Estimated Primary Completion Date February 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Relapsed/refractory CLL or relapsed/refractory SLL
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John Mei jmei@teliospharma.com
Contact: Nikki Stuart nzona@teliospharma.com
Listed Location Countries  ICMJE Hungary,   Italy,   Poland,   Russian Federation,   Ukraine,   United Kingdom,   United States
Removed Location Countries Germany
 
Administrative Information
NCT Number  ICMJE NCT02825836
Other Study ID Numbers  ICMJE MS200662_0001
2016-000286-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Telios Pharma, Inc.
Study Sponsor  ICMJE Telios Pharma, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Telios Pharma, Inc.
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP