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Chronic Lymphocytic LeukemiaPhase 1/2NCT03572634

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

A Phase 1/2 study testing TP-0903 and TP-0903 and ibrutinib combination therapy in people with Chronic Lymphocytic Leukemia and CLL, run by Sumitomo Pharma America, Inc. at 6 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia, CLL, SLL
What is being tested?
TP-0903 and TP-0903 and ibrutinib combination therapy
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
6 sitesUnited States
Study dates
10 Jun 2019to 21 Jan 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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:
  • Activated partial thromboplastin (aPTT) and prothrombin time (PT) ≤1.5 × ULN
  • Have a negative pregnancy test (if female of childbearing potential)
  • Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation and for at least 30 days after the last study drug dose. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Have read and signed the Institutional Review Board (IRB) approved informed consent form (ICF) prior to any study related procedure. (In the event that the patient is rescreened for study participation or a protocol amendment alters the care of an ongoing patient, a new ICF must be signed.)
  • Are able to comply with the requirements of the entire study

Who cannot join

  • 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
  • This exclusion criterion is not applicable to patients requiring continuation on ibrutinib. (Note: Certain patients with a rapidly rising white blood cell count while on ibrutinib may need to remain on this drug for medical reasons. These patients will need to be approved by the Medical Monitor and treated in accordance with the protocol.)
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  • 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
  • Any other cancer that has been in complete remission for 2 years or surgically cured. Medical Monitor may be contacted for additional determination of acceptable prior cancer history
  • Have known gastrointestinal disorders (eg, malabsorption syndrome), complications (eg, dysphagia), or surgery that could make consumption or absorption of oral medications problematic
  • Have an uncontrolled systemic infection (viral, bacterial, or fungal) or fever and neutropenia within 7 days prior to anticipated first dose
  • Have active and uncontrolled autoimmune cytopenias for 2 or more weeks including autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)
  • Have received prior therapy with an AXL inhibitor
  • Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation
  • Are unwilling or unable to comply with procedures required in this protocol
  • Have a history of severe adverse reaction (eg. hypersensitivity reaction, anaphylaxis) to sulfonamides

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • Duke University

    Durham, North Carolina, 27705

  • Mayo Clinic Florida

    Jacksonville, Florida, 32224

  • Cornell University

    New York, New York, 10065

  • Mayo Clinic Arizona

    Phoenix, Arizona, 85054

  • Mayo Clinic Rochester

    Rochester, Minnesota, 55905

  • Washington University - St Louis

    St Louis, Missouri, 63130

Other trials in United States

About this study

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)

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.

Read the detailed description

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.

Being tested
TP-0903, TP-0903 and ibrutinib combination therapy
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
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell, Neoplasms, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TP-0903Drug

    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.

  • TP-0903 and ibrutinib combination therapyCombination 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).

Study groups in NCT03572634
Study groupRoleWhat they receive
Group 1-TP 0903 monotherapyExperimentalAdult 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
Receives: Drug: TP-0903
Group 2-TP-0903 and ibrutinib combination therapyExperimentalAdult 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
Receives: Combination Product: TP-0903 and ibrutinib combination therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 28 days

  2. 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)

    Measured: 3 months

Secondary outcomes (4)

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

    Blood samples will be collected from patients so that derived PK parameters by non-compartment analysis may be conducted on Cycle 1

    Measured: 28 days

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

    Blood samples will be collected from patients so that derived PK parameters by non-compartment analysis may be conducted on Cycle 1

    Measured: 28 days

  3. PHASE 2: To Determine the Duration of Response

    Time from tumor response to disease progression

    Measured: 2 years

  4. PHASE 2: Rate of Overall Survival

    The time from first dose to objective tumor progression or death

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jun 2018
  2. Study start10 Jun 2019
  3. Primary completion21 Jan 2020
  4. Study completion21 Jan 2020

Why it stopped: Given the extensive time projected to conclude the study hypothesis, it is no longer feasible to include this study of TP-0903.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
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)
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03572634
Sponsor's protocol ID
TP-0903-102
Status last verified
Nov 2023
First submitted
21 May 2018
Last updated
9 Nov 2023
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing TP-0903 and TP-0903 and ibrutinib combination therapy in people with Chronic Lymphocytic Leukemia and CLL, run by Sumitomo Pharma America, Inc. at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

PHASE 1: Incidence of Dose-limiting Toxicities (DLTs) and Treatment Emergent Adverse Events. (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03572634.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Nov 2023.

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