Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL

NCT03572634 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: TP-0903-102
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Chronic Lymphocytic Leukemia; CLL; SLL; Small Lymphocytic Lymphoma

Keywords

Tolero; Phase 1/2; First in human; Previously treated Chronic Lymphocytic Leukemia (CLL); Previously treated Small Lymphocytic Lymphoma (SLL); AXL inhibitor; Cancer; Advanced Cancer; Relapsed / Refractory CLL

Outcome Measures

Primary Outcomes (2)

• PHASE 1: Incidence of Dose-limiting Toxicities (DLTs) and Treatment Emergent Adverse Events.

  A DLT is defined as a drug-related toxicity that is observed to occur within the first 28 days of treatment

  28 days

• PHASE 2: ORR in the Two Defined Patient Groups According to Guidelines Set Forth by the 2018 IWCLL

  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)

  3 months

Secondary Outcomes (4)

• PHASE 1: Area Under the Plasma Concentration-time Curve From Zero to Infinity of Oral TP-0903 in the Defined Patient Groups

  28 days

• PHASE 1: Peak Plasma Concentration (Cmax) of Oral TP-0903 in the Defined Patient Groups

  28 days

• PHASE 2: To Determine the Duration of Response

  2 years

• PHASE 2: Rate of Overall Survival

  2 years

Study Arms (2)

Group 1-TP 0903 monotherapy

EXPERIMENTAL

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

Drug: TP-0903

Group 2-TP-0903 and ibrutinib combination therapy

EXPERIMENTAL

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

Interventions

TP-0903 DRUG

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.

Group 1-TP 0903 monotherapy

TP-0903 and ibrutinib combination therapy COMBINATION_PRODUCT

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).

Group 2-TP-0903 and ibrutinib combination therapy

Eligibility Criteria

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

You may qualify if:

• Be ≥18 years old
• Have an established, pathologically confirmed diagnoses of CLL/ Small Lymphocytic Lymphoma (SLL) requiring therapy according to the 2018 IWCLL guidelines
• Have received at least one prior therapy for CLL/SLL and can be classified in one of two 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 or other investigational treatments for CLL/SLL
• 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
• Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
• Have adequate hematologic function:
• Absolute neutrophil count (ANC) ≥500/µL
• Platelet count ≥30,000/µL
• Hemoglobin ≥8 g/dL in the absence of transfusions within the previous 2 weeks
• Have adequate organ function:
• Creatinine clearance ≥30 mL/min
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤2.5 × upper limit of normal (ULN)
• Have a total bilirubin level ≤1.5 × ULN (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
• Have acceptable coagulation status:

You may not qualify if:

• Have undergone prior autologous or allogeneic stem cell transplant within ≤3 months, have not recovered from transplant associated toxicities, or requires graft versus host immunosuppressive therapy
• Have known central nervous system (CNS) involvement
• Have Richter's transformation of CLL
• Have received any monoclonal antibody therapy directed at treatment of the patient's malignancy within 2 weeks prior to anticipated first dose
• Have received any anticancer therapy including chemotherapy, radiotherapy, or an investigational anticancer drug within less than 5 half lives of the last dose of that treatment
• Have received \>20 mg/day of prednisone and 0.1 mg/day of mineralocorticoids within 7 days prior to anticipated first dose
• Have a corrected QT interval of \>450 msec (males) and \>470 msec (females) using Fridericia's correction formula
• Have a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease or any other medical condition that, in the opinion of the Investigator, would adversely affect his/her participation in the study
• Are pregnant and/or nursing, or refuse to use appropriate contraceptives during the course of the study and for at least 30 days after the last dose of study drug
• History of another malignancy in the last 5 years except for the following adequately treated:
• Local basal cell or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix or breast
• Papillary, noninvasive bladder cancer
• Early stage prostate cancer for which observation is clinically indicated
• Other Stage 1 or 2 cancers currently in complete remission

Sponsors & Collaborators

• Sumitomo Pharma America, Inc.: lead

Study Sites (6)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University - St Louis

St Louis, Missouri, 63130, United States

Location

Cornell University

New York, New York, 10065, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms; Recurrence

Interventions

dubermatinib

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

The study was stopped early (21 January 2020) due to low enrollment.

Results Point of Contact

• Title: Susan Smith
• Organization: Sr. Director Drug Development/Clinical Operations

s.smith@toleropharma.com

210-414-7702

Study Officials

• Phillip Komarnitsky

  Sumitomo Pharma America, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Model Details: 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)

Study Record Dates

• First Submitted: May 21, 2018
• First Posted: June 28, 2018
• Study Start: June 10, 2019
• Primary Completion: January 21, 2020
• Study Completion: January 21, 2020
• Last Updated: November 9, 2023
• Results First Posted: February 2, 2021

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)