Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia

NCT01914484 | Completed Phase 1 DMC

• 2 other identifiers: CAMN107ACA06TOZM-051
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients. Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II study will examine the hypothesis that combinational approach will increase response rate of resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.

Conditions

Chronic Phase Chronic Myeloid Leukemia; Accelerated Phase Chronic Myeloid Leukemia; Blastic Phase Chronic Myeloid Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Resistant to Tyrosine Kinase Inhibitor Therapy

Keywords

tyrosine kinase inhibitor resistance; chronic myeloid leukemia; acute lymphoblastic leukemia; nilotinib; ruxolitinib

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose (MTD)

  Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).

  Average of 6 months

• Phase II: Major cytogenetic response

  Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients

  Average of 6 months

Secondary Outcomes (4)

• Phase I: complete hematologic response

  Average of 3 months

• Phase I: major cytogenetic response

  Average of 6 months

• Phase I: Safety and tolerability

  Average of 6 months

• Phase II: complete hematologic response

  Average of 3 months

Other Outcomes (1)

• Phase II (exploratory): pharmacokinetic profile of combination of Nilotinib with Ruxolitinib

  During first 24 hours of first dose

Study Arms (1)

Nilotinib with Ruxolitinib

EXPERIMENTAL

Nilotinib: Given that recommended dose of Nilotinib for imatinib failed CML patients is 400mg twice daily, Nilotinib dose will remain fixed at 400mg bid throughout the cycles. Ruxolitinib: In the phase I part of the study, dose escalation will follow a 3+3 study design. Dose modifications will not occur, as the purpose of this study is to determine the maximum tolerated dose. Ruxolitinib will be given at one of 3 fixed dose levels for the duration of their treatment, either 10mg twice daily, 15mg twice daily or 20mg twice daily.

Drug: Nilotinib; Drug: Ruxolitinib

Interventions

Nilotinib DRUG

Nilotinib dose will remain fixed at 400mg bid throughout the cycles. BCR-ABL kinase inhibitor

Also known as: Tasigna

Nilotinib with Ruxolitinib

Ruxolitinib DRUG

In the phase I part of the study, dose escalation will follow a 3+3 study design at either of 3 fixed dose levels (10 mg bid, 15 mg bid or 20 mg bid). No intra-patient dose-escalation will occur. JAK inhibitor

Also known as: INCB018424, Jakavi

Nilotinib with Ruxolitinib

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 Chronic Myeloid Leukemia in any phase (CP, AP, or BP of any phenotype) or Ph+ Acute Lymphoblasic Leukemia. The confirmation of Ph+ chromosome can be substituted by the presence of BCR/ABL transcript by PCR test at diagnosis.
• Patients must be previously treated with and resistant, or intolerant, to 2 or more lines of treatment including imatinib, dasatinib, or other investigational agent. Patient who have CML-CP who were previously treated with and resistant to only dasatinib are also included. At least 2 weeks must have elapsed from the last date of treatment to the first dose of study treatment. Patients who have received Nilotinib for more than 4 consecutive weeks will be excluded.
• 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 organ liver and renal functions:
• Total bilirubin ≤ 1.5 x ULN. Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert's Disease) of grade \< 3;
• Alanine aminotransferase (ALT) ≤ 2.5x ULN or or ≤ 5.0 x ULN if considered due to leukemia.
• Creatinine ≤ 2.5 mg/dL.
• Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia;
• Serum lipase and amylase ≤ 1.5 x ULN
• Normal serum levels ≥ LLN (lower limit of normal) or corrected to within normal limits with supplements, prior to the first dose of study medication, of potassium, magnesium and calcium;
• Female patients of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test within 2 weeks prior to enrollment. Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post menopausal. Post menopausal is defined as at least 12 consecutive months without menses.
• Ability and willingness to comply with study procedures and schedule, in the Investigator's opinion.

You may not qualify if:

• Received Tyrosine Kinase Inhibitor therapy within 7 days prior to receiving the first dose of Ruxolitinib+Nilotinib, with the exception of patients who have previously received Nilotinib who must have stopped Nilotinib 4 weeks prior to receiving the first dose of Ruxolitinib+Nilotinib.
• Patients who have not recovered (\> grade 1 by NCI CTCAE, v. 4.03) from AEs (except alopecia) due to agents previously administered.
• Patients who received other therapies as follows:
• For CP and AP patients:
• Received any of the following within 2 weeks prior to receiving first dose of Ruxolitinib + Nilotinib:
• Hydroxyurea (within 7 days of first dose)
• anagrelide
• interferon
• cytarabine
• immunotherapy
• any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
• For BP patients:
• Received any of the following within 2 weeks prior to receiving first dose of Ruxolitinib + Nilotinib:
• chemotherapy other than hydroxyurea
• anagrelide

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Novartis: collaborator

Study Sites (1)

Princess Margaret Hospital / University Health Network

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Chronic-Phase; Leukemia, Myeloid, Accelerated Phase; Blast Crisis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

nilotinib; ruxolitinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cell Transformation, Neoplastic; Carcinogenesis; Neoplastic Processes; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Dennis Kim, MD/PhD

  Princess Margaret Hospital, Canada

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2013
• First Posted: August 2, 2013
• Study Start: August 1, 2013
• Primary Completion: December 31, 2018
• Study Completion: December 31, 2018
• Last Updated: November 2, 2020

Record last verified: 2020-10

Locations

CA (1)