A Study of Ponatinib in Japanese Participants With Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL)

NCT01667133 | Completed Phase 1 Results

• 1 other identifier: AP24534-11-106
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 11

Brief Summary

The purpose of this study is to assess the safety and efficacy of ponatinib in Japanese patients with chronic myeloid leukemia (CML) who have experienced failure of dasatinib or nilotinib or with Ph+ acute lymphoblastic leukemia (ALL) following failure of prior tyrosine kinase inhibitors (TKIs).

Conditions

Chronic Myeloid Leukemia (CML); Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Keywords

Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases

Outcome Measures

Primary Outcomes (3)

• Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib

  DLT was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and was defined as any of the following events: 1. Grade greater than or equal to (\>=) 3 non-hematologic, with the exception of medically controllable toxicities (example; nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting \<=3 days, but excluding alopecia; 2. Missed doses: \>25% of planned ponatinib doses over 28 days due to AEs in the first cycle; 3. Febrile neutropenia (the occurrence of an ANC \<500/microliter concurrently with a temperature elevation of \>101 degree Fahrenheit), when neutropenia is not related to underlying acute leukemia, as defined hematologic toxicity: Dose-limiting hematologic toxicity is the occurrence of a Grade 4 cytopenia \>28 days, not related to underlying disease according to the investigator. Bone marrow examination must demonstrate \<5% cellularity.

  Cycle 1 (Cycle length= 28 days)

• Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR)

  MCyR was defined as percentage of participants who achieved a complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) after the initiation of study treatment. Cytogenic response was the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells. Participants entering the study already in PCyR had to achieve a CCyR in order to be considered a success for the confirmed MCyR rate.

  Baseline up to 60 months

• Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR)

  MaHR was defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). MaHR response was confirmed by a peripheral blood complete blood count (CBC) and differential no earlier than 28 days after the response was observed. Response criteria for CHR was reported as white blood cells (WBC)\<=institutional upper limit of normal (ULN), absolute neutrophil count (ANC)\>=1000/mm\^3, platelets\>=100,000/mm\^3, no blasts or promyelocytes in peripheral blood, BM blasts \<=5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement; Response criteria for NEL reported as WBC\<=institutional ULN, no blasts or promyelocytes in peripheral blood, BM blasts \<=5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm\^3\<=platelets\<100,000/mm\^3; (ii) 500/mm\^3\<=ANC\<1000/mm\^3.

  Baseline up to 60 months

Secondary Outcomes (11)

• CP-CML Participants: Percentage of Participants With CHR

  Baseline up to 60 months

• CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR

  Baseline up to 60 months

• CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR)

  Baseline up to 60 months

• CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR)

  From the first dose of study treatment until the criteria for response were first met (up to 60 months)

• CP-CML and Advanced Phase Participants: Median Duration of Response (DOR)

  From the first assessment at which criteria for response was met until the criteria for progression was first met (up to 60 months)

Study Arms (2)

Phase 1 dose escalation

EXPERIMENTAL

Phase 1

Drug: ponatinib - Phase 1

Phase 2 expansion

EXPERIMENTAL

Phase 2

Drug: ponatinib - Phase 2

Interventions

ponatinib - Phase 1 DRUG

30 mg dose of ponatinib taken orally once daily for at least the first 6 patients. If no dose-limiting toxicities are observed, the next patients will receive 45 mg dose of ponatinib taken orally once daily. Once the recommended dose is confirmed, all patients may receive the recommended dose, at the investigators' discretion.

Also known as: AP24534

Phase 1 dose escalation

ponatinib - Phase 2 DRUG

Recommended dose of ponatinib as determined in the dose escalation phase. In addition, 3 patients will receive 15 mg dose once daily for 8 days for PK testing. These PK patients may be allowed to receive the recommended dose after PK testing is complete, at the investigators' discretion.

Also known as: AP24534

Phase 2 expansion

Eligibility Criteria

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

You may qualify if:

• Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL, as follows:
• All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to beginning treatment.
• Examination of at least 20 metaphases is required in patients in CP. If less than 20 metaphases are examined, the BM aspirate must be repeated.
• Adequate BM aspirate with differential cell counts is required in patients with AP, BP, or Ph+ ALL. If an adequate aspirate is not obtained, the aspirate must be repeated.
• Be previously treated with and resistant, or intolerant, as defined in the protocol, to either dasatinib or nilotinib for CML or at least one TKI for Ph+ ALL, regardless of whether dasatinib or nilotinib or the prior TKI were used to treat newly diagnosed or resistant patients.
• Must be ≥ 18 years old.
• Provide written informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Minimum life expectancy of 3 months or more.
• Adequate renal function defined as serum creatinine \< 1.5 × upper limit of normal (ULN) for institution.
• Adequate hepatic function defined as:
• Total bilirubin \< 1.5 × ULN
• Alanine aminotransferase (ALT \[SGPT\]) and aspartate aminotransferase (AST \[SGOT\]) \< 2.5 × ULN for institution (\< 5 × ULN if liver involvement with leukemia)
• Prothrombin time \< 1.5 × ULN
• Normal pancreatic status defined as:

You may not qualify if:

• Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (\> grade 1 by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 \[NCI CTCAE v.4.0\]) from adverse events (AEs) (except alopecia) due to agents previously administered.
• Received other therapies as follows:
• For CP and AP patients, received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
• For BP patients, received chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies.
• For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib and other chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies.
• All patients are excluded if they have not recovered (\> grade 1 by NCI CTCAE v.4.0) from AEs (except alopecia) due to agents previously administered.
• Underwent autologous or allogeneic stem cell transplant \< 60 days prior to receiving the first dose of ponatinib; any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
• Take medications that are known to be associated with Torsades de Pointes.
• Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
• Have previously been treated with ponatinib.
• Patients with CP-CML are excluded if they are in CCyR.
• Patients with CP-CML are excluded if a baseline BM aspirate adequate for conventional cytogenetic analysis with 20 metaphases examined is not available.
• Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR.
• Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM aspirate adequate for cell count and differential report is not available. Patients with a fibrotic marrow or dry tap that does not yield adequate cell counts for diagnosis are not evaluable for classification, and endpoints are not eligible.
• Have significant or active cardiovascular disease, specifically including, but not restricted to:

Sponsors & Collaborators

• Ariad Pharmaceuticals: lead

Study Sites (11)

Aichi Cancer Center Hospital

Nagoya, Aichi-ken, 464-8681, Japan

Location

Akita University Hospital

Akita, Akita, 010-8543, Japan

Location

Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital

Hiroshima, Hiroshima, 730-8619, Japan

Location

Kyushu University Hospital

Hukuoka-shi, Hukuoka, Japan

Location

Kinki University Hospital, Faculty of Medicine

Osakasayama-shi, Osaka, 589-8511, Japan

Location

The Cancer Institute Hospital Japanese Foundation for Cancer Research

Koto, Tokyo, Japan

Location

The University of Tokyo, The Institute of Medical Science

Minato-ku, Tokyo, Japan

Location

Keio University Hospital

Shinjuku-ku, Tokyo, Japan

Location

Osaka City University Hospital

Shinjuku-ku, Tokyo, Japan

Location

National Cancer Center Hospital

Chuo-ku, Tokyo, Japan

Location

Tokyo Medical University Hospital

Shinjuku-ku, Tokyo, Japan

Location

Related Publications (2)

• Hanley MJ, Diderichsen PM, Narasimhan N, Srivastava S, Gupta N, Venkatakrishnan K. Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development. J Clin Pharmacol. 2022 Apr;62(4):555-567. doi: 10.1002/jcph.1990. Epub 2021 Dec 16.

  PMID: 34699069 DERIVED

• Tojo A, Kyo T, Yamamoto K, Nakamae H, Takahashi N, Kobayashi Y, Tauchi T, Okamoto S, Miyamura K, Hatake K, Iwasaki H, Matsumura I, Usui N, Naoe T, Tugnait M, Narasimhan NI, Lustgarten S, Farin H, Haluska F, Ohyashiki K. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol. 2017 Sep;106(3):385-397. doi: 10.1007/s12185-017-2238-9. Epub 2017 Apr 25.

  PMID: 28444644 DERIVED

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia; Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases

Interventions

ponatinib

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: August 13, 2012
• First Posted: August 17, 2012
• Study Start: August 31, 2012
• Primary Completion: August 2, 2018
• Study Completion: August 2, 2018
• Last Updated: June 13, 2022
• Results First Posted: June 13, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

JP (11)