Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL
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|ClinicalTrials.gov Identifier: NCT03572634|
Recruitment Status : Recruiting
First Posted : June 28, 2018
Last Update Posted : April 1, 2019
TP-0903 is an inhibitor of AXL kinase. TP-0903 has shown potent inhibition of AXL kinase and other TAM family members in a biochemical kinase assay. TP-0903 demonstrates corresponding activity in cancer cell lines and mouse xenograft efficacy models. TP-0903 is shown to block cancer cell epithelial-to-mesenchymal transitions. AXL was identified as a potential therapeutic target in chronic lymphocytic leukemia (CLL). TP 0903 was shown to induce apoptosis in CLL B-cells taken directly from patients.TP-0903 was equally potent against CLL cells regardless of risk-factor.
TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. TP-0903 has demonstrated profound single agent activity in CLL B cells taken directly from patients even if the patient has high risk factors (ie, 17p/P53 deletions) or progressed on other agents (ie, ibrutinib). TP-0903 is currently being evaluated in patients with refractory solid tumors (TP-0903-101). This proposed study is designed to identify the maximum tolerated dose (MTD), safety profile and recommended Phase 2 dose (RP2D) of TP-0903 in patients with previously treated CLL. Treatment cycles may be repeated if the patient continues to show benefit and if TP-0903 is reasonably well tolerated.
The study will investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903.
|Condition or disease||Intervention/treatment||Phase|
|Chronic Lymphocytic Leukemia CLL SLL Small Lymphocytic Lymphoma||Drug: TP-0903 Combination Product: TP-0903 and ibrutinib combination therapy||Phase 1 Phase 2|
This is a combined Phase 1/2 study of oral TP-0903 in patients with previously treated CLL/SLL. In both Phase 1 and Phase 2, study participants will be assigned to one of two defined patient groups:
- Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are intolerant to, or have progressed on, B-cell receptor antagonists and/or BCL-2 antagonists
- Group 2 (TP-0903 and ibrutinib combination therapy): Patients with CLL/SLL who have progressed on ibrutinib yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient.
Both groups of patients will be treated identically with TP 0903 and will undergo the same study assessments.
Phase 1 Patients will be enrolled in Group 1 and Group 2 in cohorts of 3 to 6 patients simultaneously. Group 2 will start at one dose level below the Group 1 starting dose. In each group, escalation of the TP-0903 dose will follow a standard 3+3 design with sequential cohorts of three patients treated with incrementally higher doses of TP 0903 until a dose-limiting toxicity (DLT) is observed and the maximum tolerated dose (MTD) is established. In the absence of DLTs, the dose will be increased using a modified Fibonacci dose escalation scheme.
Once the MTD or preliminary RP2D is identified, an expansion cohort of up to 6 patients will be enrolled in each patient group to confirm safety/suitability of the preliminary RP2D, to collect additional biomarker data, and to further explore efficacy.
It is expected that up to 27 patients will be enrolled in each patient group for a total of up to 54 patients (TP-0903 monotherapy and combination therapy with ibrutinib).
Additional dose levels, schedules, or disease indications of TP 0903 may be explored, as appropriate, based on the modulation of key biomarkers and the safety profile and clinical signals of activity.
Phase 2 In Phase 2, patients will be enrolled in Group 1 (TP 0903 monotherapy) and Group 2 (TP-0903 combination therapy with ibrutinib) based on the Simon 2 stage design. In Stage 1, up to 13 patients will be enrolled into each patient group (total of 26 patients). If there are no responses among these 13 patients in each group, the study will be stopped. Otherwise, Stage 2 will open to enroll 14 additional patients in each group for a total of 27 patients per group. If 4 or more responses are observed among 27 patients, the conclusion will be that the study treatment is worthy of further investigation.
If both patient groups enroll through Stage 2, it is anticipated that the total enrollment for Phase 2 will be 54 patients.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||108 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||
Adult patients with CLL/SLL who:
are intolerant to, or have had progressive disease on B-cell receptor antagonists, BCL-2 antagonists or other investigational treatments for CLL/SLL (Group 1-TP 0903 monotherapy); or have progression of disease on ibrutinib, yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient (Group 2-TP-0903 and ibrutinib combination therapy)
|Masking:||None (Open Label)|
|Official Title:||A Combined Phase 1/2 Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of TP-0903 in Patients With Previously Treated Chronic Lymphocytic Leukemia (CLL)|
|Actual Study Start Date :||November 20, 2018|
|Estimated Primary Completion Date :||January 2021|
|Estimated Study Completion Date :||April 2021|
Experimental: Group 1-TP 0903 monotherapy
Adult patients with CLL/SLL who:
are intolerant to, or have had progressive disease on B-cell receptor antagonists, BCL-2 antagonists or other investigational treatments for CLL/SLL
Monotherapy: PHASE 1: TP-0903 will be a 25 mg flat dose. The study drug will be administered orally once daily for 28 days (each cycle is 28 days; no drug-free period).
Patients may continue to receive TP-0903 in 28-day cycles at the same dose given during Cycle 1 until they experience unacceptable toxicity or unequivocal disease progression. No intrapatient escalation of the TP-0903 dose is permitted.
PHASE 2: The starting dose of TP-0903 will be the RP2D determined during Phase 1. TP 0903 will be administered orally at a fixed dose once daily for 28 days (each cycle is 28 days; no drug-free period) with repeated cycles permitted until a patient experiences unacceptable toxicity or unequivocal disease progression.
Experimental: Group 2-TP-0903 and ibrutinib combination therapy
Adult patients with CLL/SLL who:
have progression of disease on ibrutinib, yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient
Combination Product: TP-0903 and ibrutinib combination therapy
Combination therapy: PHASE 1: TP-0903 and ibrutinib combination therapy: The starting dose of TP-0903 will be a 20 mg flat dose. TP-0903 will be administered orally once daily for 28 days (each cycle is 28 days; no drug-free period). Patients will also receive ibrutinib at the same dose that they were receiving immediately prior to study enrollment.
Patients should continue with the combination of ibrutinib and TP-0903 for at least 3 months after study start.
PHASE 2: The starting dose of TP-0903 will be the RP2D determined during Phase 1. Patients will also receive ibrutinib at the same dose that they were receiving immediately prior to study enrollment. Both TP 0903 and ibrutinib will be administered orally at fixed doses once daily for 28 days (each cycle is 28 days; no drug-free period).
- PHASE 1: Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events. [ Time Frame: 28 days ]A DLT is defined as a drug-related toxicity that is observed to occur within the first 28 days of treatment
- PHASE 2: ORR in the two defined patient groups according to guidelines set forth by the 2018 IWCLL [ Time Frame: 3 months ]Objective Response Rate ([ORR], ie, rate of complete response [CR] plus rate of partial response [PR] in the defined patient groups according to guidelines set forth by the 2018 International Workshop on CLL (IWCLL)
- PHASE 1: Area under the plasma concentration-time curve from zero to infinity of oral TP-0903 in the defined patient groups [ Time Frame: 28 days ]Blood samples will be collected from patients so that derived PK parameters by non-compartment analysis may be conducted on Cycle 1
- PHASE 1: Peak plasma concentration (Cmax) of oral TP-0903 in the defined patient groups [ Time Frame: 28 days ]Blood samples will be collected from patients so that derived PK parameters by non-compartment analysis may be conducted on Cycle 1
- PHASE 2: To determine the Duration of Response [ Time Frame: 2 years ]Time from tumor response to disease progression
- PHASE 2: Rate of overall survival [ Time Frame: 2 years ]The time from first dose to objective tumor progression or death
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03572634
|Contact: Holly Beever, BS, RNfirstname.lastname@example.org|
|Contact: Susan Smith, MSNemail@example.com|
|United States, Arizona|
|Mayo Clinic Arizona||Recruiting|
|Phoenix, Arizona, United States, 85054|
|Contact: Meline Arzumanyan 480-342-2082|
|Principal Investigator: Jose Leis, MD|
|United States, Florida|
|Mayo Clinic Florida||Recruiting|
|Jacksonville, Florida, United States, 32224|
|Contact: Rachel Pop 904-953-8401|
|Principal Investigator: Asher Chanan-Khan, MD|
|United States, Minnesota|
|Mayo Clinic Rochester||Recruiting|
|Rochester, Minnesota, United States, 55905|
|Contact: Neil Kay, MD 507-284-2511|
|Principal Investigator: Neil Kay, MD|
|United States, Missouri|
|Washington University - St Louis||Recruiting|
|Saint Louis, Missouri, United States, 63130|
|Contact: Nancy Borror 314-362-3257|
|Principal Investigator: Brad Kahl, MD|
|United States, New York|
|Cornell University||Not yet recruiting|
|New York, New York, United States, 10065|
|Contact: Rita Vaccaro, RN 212-746-0702|
|Principal Investigator: John Allan, MD|
|United States, North Carolina|
|Duke University||Not yet recruiting|
|Durham, North Carolina, United States, 27705|
|Contact: Danielle Brander, MD 919-684-8964|
|Principal Investigator: Danielle Brander, MD|
|Study Director:||Margit Janat-Amsbury, MD, PhD||Tolero Pharmaceuticals|