A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02081378
Collaborator
(none)
326
Enrollment
19
Locations
5
Arms
118.7
Anticipated Duration (Months)
17.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The design of a phase I, open label, dose finding study was chosen in order to establish a safe and tolerated dose of single agent ABL001 in CML and Ph+ ALL patients who are relapsed or refractory to or are intolerant of TKIs, and of ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib in Ph positive CML patients who are relapsed or refractory to TKIs.

Detailed Description

This first-in-human trial with ABL001 is a dose escalation study whose primary purpose is to estimate the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of single agent ABL001 in CML or Ph+ ALL patients, and in combination with either Nilotinib or Imatinib or Dasatinib in Ph positive CML patients. The safety, tolerability and pharmacokinetic (PK) profile of ABL001 and ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib will be assessed together with an evaluation of pharmacodynamic (PD) changes in peripheral blood mononuclear cells (PBMC) and bone marrow aspirates and all data may contribute to the assessment of the RDE.

An understanding of the MTD/RDE, safety profile, PK/PD relationship, and preliminary evidence of anti-CML and ALL activity will be used to inform future development in adults with CML and Ph+ ALL. By virtue of its distinct pharmacological profile and by preclinical pharmacological studies demonstrating an additive effect, a combination of ABL001 and a tyrosine-kinase inhibitor (TKI) has the potential to achieve a deeper molecular response in a higher proportion of CML patients as compared to single agent TKI therapy. Such a combination has the added advantage of targeting the ABL kinase domain at two distinct locations, theoretically preventing single point mutation-associated treatment resistance. The prediction is that a nilotinib+ABL001, imatinib+ABL001 and/or dasatinib+ABL001 combination will increase the percentage of patients who achieve a complete molecular response (CMR) and decrease the time to CMR, thereby increasing the possibility of achieving sustained treatment-free remissions in these patients. In addition, some patients may be intolerant of therapy with TKIs or may develop mutations that promote resistance to TKI therapy. In these patients, ABL001 may provide a novel therapeutic option.

Study Design

Study Type:
Interventional
Actual Enrollment :
326 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Multicenter, Open-label Study of Oral ABL001 in Patients With Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Actual Study Start Date :
Apr 24, 2014
Anticipated Primary Completion Date :
Mar 14, 2024
Anticipated Study Completion Date :
Mar 14, 2024

Arms and Interventions

ArmIntervention/Treatment
Experimental: ABL001 in CML patients

Dose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with CML

Drug: ABL001
ABL001 will be administered orally in a dose escalation schedule.

Experimental: ABL001+Nilotinib in CML patients

Dose escalation study to estimate the MTD and/or RDE of ABL001 in combination with Nilotinib in adult CML patients

Drug: ABL001 + Nilotinib
ABL001 and Nilotinib will be administered orally in CML patients

Experimental: ABL001 in Ph+ ALL patients

Dose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with Ph positive ALL patients

Drug: ABL001
ABL001 will be administered orally in Ph+ ALL patients

Experimental: ABL001+Imatinib in CML patients

Dose escalation study to estimate the MTD and/or RDE of ABL001 in combination with imatinib in adult CML patients

Drug: ABL001+imatinib
ABL001 and imatinib will be administered orally in CML patients

Experimental: ABL001+dasatinib in CML patients

Dose escalation study to estimate the MTD and/or RDE of ABL001 in combination with dasatinib in adult CML patients

Drug: ABL001+dasatinib
ABL001+dasatinib will be administered orally in CML patients

Outcome Measures

Primary Outcome Measures

  1. Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment [First Cycle is 28 days]

    Determine the MTD and/or RDE of ABL001 as single agent in CML and Ph+ ALL, and in combination with either nilotinib or imatinib or dasatinib in CML patients

Secondary Outcome Measures

  1. Hematologic Response [At screening and first day of cycle 2 and 3 and every 12 weeks afterwards]

  2. Cytogenetic response [at screening or when a patient's BCR-ABL ratio has risen to >1%]

  3. BCR-ABL transcript level [At screening and first day of cycle 2 and 3 and every 12 weeks afterwards]

  4. Cmax of ABL001 as measured in plasma [Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.]

  5. Cmin of ABL001 as measured in plasma [Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.]

  6. AUCinf of ABL001 as measured in plasma [Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.]

  7. AUClast of ABL001 as measured in plasma [Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.]

  8. AUCtau of ABL001 as measured in plasma [Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.]

  9. T1/2 of ABL001 as measured in plasma [Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.]

  10. Adverse events [Collected from screening visit through post-treatment follow-up period]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
For CML patients either:
    1. Patients with Ph+ CML in chronic or accelerated phase who were previously treated with at least two different tyrosine kinase inhibitors prior to study entry and are relapsed, refractory to or intolerant of TKIs as determined by investigators or
    1. Patients with CML in chronic or accelerated phase who exhibit relapsed disease associated with the presence of the T315I "gatekeeper mutation" after at least one TKI are also eligible provided that no other effective therapy exists
For ALL and CML-BP patients:
  • Patients with CML BP or Ph+ ALL who have a cytopathologically confirmed diagnosis and are relapsed or refractory to at least one prior TKI or intolerant of TKIs. TKI failure for Ph+ ALL and CML-BP patients is defined as at least the loss of Molecular Response (MR) 4.5 (BCR-ABL ≤ 0.0032%)

  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

  • Willingness and ability to comply with all study procedures

  • Written informed consent obtained prior to any screening procedures

Exclusion Criteria:
Wash-out period:
  • Systemic antineoplastic therapy (including cytotoxic chemotherapy, alfa-interferon and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment

  • Therapy with TKIs as single agent within 5 half-lives before the first dose of study treatment

  • Unconjugated monoclonal antibody therapies within 28 days or 5 half-lives, whichever is shorter, before the first dose of study treatment

  • For patients receiving ABL001 in combination with either nilotinib or imatinib or dasatinib, intolerance to nilotinib, imatinib or dasatinib, respectively

  • Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment.

  • CNS irradiation for meningeal leukemia, except if radiotherapy occurred > 3 months previously. At least four weeks must have elapsed since prophylactic CNS irradiation given as part of a front-line therapy regimen for ALL

  • Major surgery within 2 weeks before the first dose of study treatment

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Dana Farber Cancer Institute Hematology / OncologyBostonMassachusettsUnited States02215
2University of Michigan Comprehensive Cancer Center SCAnn ArborMichiganUnited States48109
3Memorial Sloan Kettering Cancer Center Memorial Sloan KetteringNew YorkNew YorkUnited States10065
4Oregon Health and Science University SC-6PortlandOregonUnited States97239
5University of Texas/MD Anderson Cancer Center UT MD AndersonHoustonTexasUnited States77030-4009
6Huntsman Cancer Institute SCSalt Lake CityUtahUnited States84112
7Novartis Investigative SiteAdelaideSouth AustraliaAustralia5000
8Novartis Investigative SiteParis Cedex 10Cedex 10France75475
9Novartis Investigative SiteBordeauxFrance33076
10Novartis Investigative SiteBerlinGermany13353
11Novartis Investigative SiteFrankfurtGermany60590
12Novartis Investigative SiteJenaGermany07740
13Novartis Investigative SiteRomaRMItaly00161
14Novartis Investigative SiteKobe-shiHyogoJapan650-0017
15Novartis Investigative SiteUijeongbu siGyeonggi DoKorea, Republic of11759
16Novartis Investigative SiteSeoulSeocho GuKorea, Republic of06591
17Novartis Investigative SiteAmsterdamNetherlands1081 HV
18Novartis Investigative SiteSingaporeSingapore169608
19Novartis Investigative SiteMadridSpain28006

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02081378
Other Study ID Numbers:
  • CABL001X2101
First Posted:
Mar 7, 2014
Last Update Posted:
Jan 12, 2022
Last Verified:
Jan 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jan 12, 2022