An Open-Label, Phase I/II Study of Nilotinib (Tasigna) and MEK-162 (ARRY-162) Used in Combination for Patients With Refractory or Advanced Chronic Myeloid Leukemia and Philadelphia Positive Acute Leukemia (Protocol CAMN107AUS41T)

NCT02225574 | Terminated Phase 1 FDA Drug

• 2 other identifiers: 2014-0128NCI-2015-00044
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to find the highest tolerated dose of the combination of nilotinib and MEK-162 that can be given to patients with CML or acute leukemia. Researchers also want to learn if the drug combination can help to control the disease. The safety of the drug combination will also be studied.

Conditions

Leukemia

Keywords

Leukemia; Advanced phase chronic myeloid leukemia; refractory chronic phase chronic myeloid leukemia; CML; Accelerated phase; (AP); Blast phase; (BP); Philadelphia-positive acute leukemia; MEK-162; Nilotinib; AMN107; Tasigna; Questionnaires; Surveys

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of MEK-162 and Nilotinib

  MTD defined as maximum daily oral dose at which \<33% of patients experience a dose limiting toxicity (DLT) during first 28 days. DLT defined by events that are clinically significant and at least possibly related to study drug occurring during the first 4 weeks of therapy. Toxicities reported on a scale of 1-4 according to the NCI criteria Common Terminology Criteria for Adverse Events (CTCAE).

  28 days

Secondary Outcomes (2)

• Response Rate for Advanced CML and Philadelphia-Positive Acute Leukemia

  28 days

• Response Rate for Chronic Phase CML

  After 3, 28 day cycles

Study Arms (2)

Advanced CML + Philadelphia positive Acute Leukemia-Group 1

EXPERIMENTAL

Phase 1 Starting dose of MEK-162: 30 mg by mouth twice a day of a 28 day cycle. Phase 1 Starting dose of Nilotinib: 400 mg by mouth twice a day of a 28 day cycle. Questionnaires completed and the end of cycle 1, 2, 3, 6, 9, and 12. Phase 2 Starting dose of MEK-162: MTD from Phase 1 to be taken by mouth twice a day starting on Day 1 of a 28 day cycle. Phase 2 Starting dose of Nilotinib: MTD from Phase 1 to be taken by mouth twice a day starting on Day 2 of a 28 day cycle.

Drug: MEK-162; Drug: Nilotinib; Behavioral: Questionnaires

Chronic Phase CML - Group 2

EXPERIMENTAL

Phase 1 Starting dose of MEK-162: 30 mg by mouth twice a day of a 28 day cycle. Phase 1 Starting dose of Nilotinib: 400 mg by mouth twice a day of a 28 day cycle. Questionnaires completed and the end of cycle 1, 2, 3, 6, 9, and 12. Phase 2 Starting Dose of Nilotinib: MTD from Phase 1 by mouth twice a day starting on Day 1 of a 28 day cycle. Phase 2 Starting Dose of MEK-162: MTD from Phase 1 by mouth twice a day starting on Day 8 of a 28 day cycle.

Drug: MEK-162; Drug: Nilotinib; Behavioral: Questionnaires

Interventions

MEK-162 DRUG

Phase 1: Advanced CML + Philadelphia positive Acute Leukemia-Group 1 Starting Dose of MEK-162: 30 mg by mouth twice a day on starting on Day 1 of a 28 day cycle. Phase 2 Advanced CML + Philadelphia positive Acute Leukemia-Group 1 Starting dose of MEK-162: MTD from Phase 1 to be taken by mouth twice a day starting on on Day 1 of a 28 day cycle. Phase 1 Chronic Phase CML - Group 2 Starting dose of MEK-162: 30 mg by mouth twice a day of a 28 day cycle. Phase 2 Chronic Phase CML - Group 2 Starting Dose of MEK-162: MTD from Phase 1 by mouth twice a day starting on Day 8 of a 28 day cycle.

Advanced CML + Philadelphia positive Acute Leukemia-Group 1; Chronic Phase CML - Group 2

Nilotinib DRUG

Phase 1 Advanced CML + Philadelphia positive Acute Leukemia-Group 1 Starting Dose of Nilotinib: 400 mg by mouth twice a day of a 28 day cycle. Phase 2 Advanced CML + Philadelphia positive Acute Leukemia-Group 1 Starting dose of Nilotinib: MTD from Phase 1 to be taken by mouth twice a day starting on Day 2 of a 28 day cycle. Phase 1 Chronic Phase CML - Group 2 Starting dose of Nilotinib: 400 mg by mouth twice a day of a 28 day cycle. Phase 2 Chronic Phase CML - Group 2 Starting Dose of Nilotinib: MTD from Phase 1 by mouth twice a day starting on Day 1 of a 28 day cycle.

Also known as: AMN107, Tasigna

Advanced CML + Philadelphia positive Acute Leukemia-Group 1; Chronic Phase CML - Group 2

Questionnaires BEHAVIORAL

Questionnaires completed and the end of cycle 1, 2, 3, 6, 9, and 12.

Also known as: Surveys

Advanced CML + Philadelphia positive Acute Leukemia-Group 1; Chronic Phase CML - Group 2

Eligibility Criteria

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

You may qualify if:

• Patients 18 years of age or older with advanced CML (CML-AP, CML-BP and Philadelphia chromosome-positive acute leukemia) or refractory chronic phase CML are eligible, as defined as follows: The phase I portion of the study will be conducted first in advanced phase (accelerated phase CML, blast phase CML or Philadelphia-positive acute leukemia) patients. Once MTD is identified, a cohort of 6 patients with CML chronic phase who have failed prior therapy with at least two tyrosine kinase inhibitor will be treated at the MTD to determine if this dose is also acceptable for chronic phase patients. The phase II will be conducted in two treatment arms as follows: Treatment Arm A (Advanced phase disease) and treatment Arm B (Therapy for CP-CML refractory/resistant/suboptimally responding to at least two prior TKI's)
• Patients with advanced phase CML or acute leukemia must have failed at least one prior TKI. Patients with chronic phase CML must have failed, have resistance or suboptimal response to at least two tyrosine kinase inhibitors, or have intolerance to two prior tyrosine kinase inhibitors. For patient with prior intolerance, they should have received at least 2 TKI and experienced intolerance to one TKI and resistance/suboptimal
• Patients with cytogenetic BCR-Abl variants and additional chromosomal abnormalities ('clonal evolution') will be eligible. Cytogenetics to be performed, but results are not required to start therapy in patients with hematologic progression
• Patients who have failed nilotinib, including those who are refractory to nilotinib at any dose or have relapsed on nilotinib at any dose will be eligible for the study. Patients currently on nilotinib will continue on their prescribed dose of nilotinib and MEK-162 will be added based on the current cohort level in phase I or at the established MTD in phase II. In the instance the nilotinib dose is greater than the current cohort (in phase 1) or the MTD (in phase 2) patients will be dose reduced to the dosage as prescribed by protocol and then dose escalated as allowed in protocol at the PIs discretion.
• For the phase I portion of the study, patients who had received prior therapy with nilotinib should have been able to tolerate the dose equivalent to the starting dose of nilotinib in the dose level at which the patient is being entered. Patients who previously received nilotinib but never at the dose being proposed are eligible provided they tolerated the maximum dose they were prescribed with no grade 3 or 4 toxicity not responding to optimal management.
• Patients must have been off all prior therapy for CML for 2 weeks prior to start of study therapy and recovered from the toxic effects of that therapy. Exceptions to these are hydroxyurea and TKIs (including but not limited to imatinib, nilotinib, dasatinib, ponatinib and bosutinib), which should be discontinued ≥48 hrs prior to the start of therapy. Patients who are receiving nilotinib prior to enrollment do not have to discontinue this agent prior to start of study therapy
• Eastern Cooperative Oncology Group (ECOG) performance status \</=2
• Men and women of childbearing potential should practice effective methods of contraception. Men and women of childbearing potential are defined as: a male that has not been surgically sterilized or female that has not been amenorrheic for at least 12 consecutive months or that has not been surgically sterilized. Patients must use birth control during the study and for 3 months after the last dose of study drug if they are sexually active.
• Adequate organ function: Serum creatinine \</=2.0 mg/dl or creatinine clearance \>/=60 mL/min, Direct bilirubin \</=2.0xULN (unless considered due to leukemia involvement), Alanine aminotransferase (ALT) \</=2.5xULN (\</=5.0xULN if considered due to leukemic involvement.)
• Adequate cardiac function: left ventricular ejection fraction (LVEF) \>/= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram, QTc interval \</= 480 ms;
• Women of childbearing potential must have a pregnancy test at screening.
• Signed informed consent.

You may not qualify if:

• Impaired cardiac function including any one of the following: a. Inability to monitor the QT interval on ECG b. Congenital long QT syndrome or a known family history of long QT syndrome. c. Clinically significant resting brachycardia (\<45 beats per minute) d. QTc \> 480 msec on baseline ECG. If QTc \>450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc e. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \<6 months prior to screening, Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \<6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
• History of Gilbert's syndrome.
• Uncontrolled arterial hypertension despite medical treatment
• Prior therapy with a MEK- inhibitor
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
• History of retinal degenerative disease;
• Patients with washout period \< 6 weeks from the last dose of ipilimumab or other immunotherapy
• Known positive serology for HIV, active hepatitis B, and/or active hepatitis C infection
• Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment
• Patients currently receiving treatment with strong CYP3A4 inhibitors who cannot discontinue such treatment or be switched to a different medication prior to starting study drug are excluded from study entry. Strong CYP3A4 inhibitors include the following medications: itraconazole, ketoconazole, miconazole, voriconazole; amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir; ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, isoniazid, ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin.
• Patients receiving treatment with any medications that have the potential to prolong the QT interval who cannot discontinue such treatment or be switched to a different medication prior to starting study drug are excluded from the study entry. A list of anti-arrhythmic drugs and other drugs that may prolong the QT interval is added in protocol section 8.5 (page 53).
• Impaired gastrointestinal (GI) function or active GI disease that may significantly alter the absorption of study drug in the opinion of the treating physician (e.g., active ulcerative diseases, uncontrolled nausea, uncontrolled vomiting, uncontrolled diarrhea, active malabsorption syndrome, small bowel resection within last 1 year or gastric bypass surgery within last 1 year).
• Another active primary malignant disease, which requires systemic treatment (chemotherapy or radiation)
• History of significant congenital or acquired bleeding disorder unrelated to cancer

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Array BioPharma: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid, Chronic-Phase; Blast Crisis

Interventions

binimetinib; nilotinib; Surveys and Questionnaires

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cell Transformation, Neoplastic; Carcinogenesis; Neoplastic Processes

Intervention Hierarchy (Ancestors)

Data Collection; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Naval Daver, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: August 22, 2014
• First Posted: August 26, 2014
• Study Start: March 11, 2015
• Primary Completion: February 2, 2017
• Study Completion: February 2, 2017
• Last Updated: February 12, 2020

Record last verified: 2020-02

Locations

US (1)