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A Study Comparing Ponatinib and Nilotinib in Participants With Chronic Myeloid Leukemia (OPTIC-2L)

Primary Purpose

Chronic Phase Chronic Myeloid Leukemia

Status

Terminated

Phase

Phase 3

Locations

Belgium

Study Type

Interventional

Intervention

Ponatinib 30 mg QD

Ponatinib 15 mg QD

Nilotinib 400 mg BID

About this trial

This is an interventional treatment trial for Chronic Phase Chronic Myeloid Leukemia focused on measuring CML, CP-CML, Leukemia, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms by Histologic Type, Neoplasms, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Have CP-CML and are resistant to first-line imatinib treatment.
Be male or female ≥18 years old.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Have adequate renal function as defined by the following criterion:
• Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution.
Have adequate hepatic function as defined by all of the following criteria:
- Total serum bilirubin ≤1.5 × ULN, unless due to Gilbert's syndrome
- Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present
- Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present.
Have normal pancreatic status as defined by the following criterion:
- Serum lipase and amylase ≤1.5 × ULN.

Exclusion Criteria:

Have previously been treated with any approved or investigational TKIs other than imatinib or treated with imatinib within 14 days prior to receiving study drug.
Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy.
Underwent autologous or allogeneic stem cell transplant.
Are in CCyR or MMR.
Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
- Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (TIA)
- Any history of peripheral vascular infarction, including visceral infarction
- Any history of a revascularization procedure, including vascular surgery or the placement of a stent
- History of venous thromboembolism, including deep venous thrombosis, superficial venous thrombosis, or pulmonary embolism, within 6 months prior to enrollment
- Congestive heart failure (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than 45% or less than the institutional lower limit of normal (whichever is higher) within 6 months prior to enrollment.

Sites / Locations

Cliniques Universitaire Saint-Luc (Site 058)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Cohort A: Ponatinib 30 mg

Cohort B: Ponatinib 15 mg

Cohort C: Nilotinib 400 mg

Arm Description

Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 42 months.

Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 45 months.

Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.

Outcomes

Primary Outcome Measures

Percentage of Participants With Major Molecular Response (MMR)

MMR is defined as the percentage of participants achieving a ratio of ≤0.1% Breakpoint Cluster Region-Abelson (BCR ABL) to ABL transcripts on the international scale (≤0.1% BCR-ABL/ABL[IS]) at any time within 12 months after randomization.

Secondary Outcome Measures

Percentage of Participants With Major Cytogenetic Response (MCyR)

MCyR was the percentage of participants achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) or Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow) at any time within 12 months after randomization.

Percentage of Participants With Complete Cytogenetic Response (CCyR)

CCyR rate was defined as the percentage of participants achieving CCyR up to 12 months after randomization. CCyR is defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow.

Percentage of Participants With Molecular Response (MR)

Molecular response rate is defined as percentage of participants achieving MR2: Molecular response with 2-log reduction (defined as ≤1% BCR-ABL[IS]), MMR: Major molecular responder, MR4 (defined as ≤0.01% BCR-ABL[IS]), and MR4.5 (defined as ≤0.0032% BCR-ABL[IS]) after randomization.

Percentage of Participants With MR1

MR1 was defined as the percentage of participants achieving a ratio of ≤10% BCR ABL to ABL transcripts on the international scale at 3 months.

Percentage of Participants With Treatment Emergent Arterial Occlusive Events (TE-AOEs), Treatment Emergent Venous Thromboembolic Events (TE-VTE), Adverse Events (AEs), and Serious AEs (SAEs)

TE-AOE: arterial occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. TE-VTE: vascular occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. AE: any untoward medical occurrence in participant administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is congenital anomaly/birth defect/is medically important event.

Time to Response

Time to MMR defined as the interval between the randomization date and the first date at which the criteria for response was met. MMR was defined as <=0.1% BCR-ABL.

Duration of Response

Duration of response defined as the interval between the first assessment at which the criteria for response was met until the earliest date at which loss of response occurs, or the criteria for progression was met.

Progression-free Survival (PFS)

Progression-free survival (PFS) defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression was met (progression to AP- or BP CML), or death due to any cause, censored at the last response assessment.

Overall Survival

Overall survival (OS) defined as the interval between the first dose date of study treatment and date of death due to any cause, censored at the last contact date to be alive.

Percentage of Participants Who Achieved/Maintained Complete Hematologic Response (CHR)

CHR rate is defined as the percentage of participants achieving CHR at any time after initiation of study treatment. CHR is defined as achieving all of the following measurements: White blood cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets <450 x 10^9/L; No blasts or promyelocytes in peripheral blood; <5% myelocytes plus metamyelocytes in peripheral blood; Basophils in peripheral blood <5%; No extramedullary involvement (including no hepatomegaly or splenomegaly).

Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption

An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

Percentage of Participants With Progression to Accelerated Phase (AP) or Blast Phase (BP)-CML

Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*10^9 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP-CML is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Full Information

NCT ID

NCT02627677

First Posted

August 13, 2015

Last Updated

October 28, 2021

Sponsor

Ariad Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02627677

Brief Title

A Study Comparing Ponatinib and Nilotinib in Participants With Chronic Myeloid Leukemia

Acronym

OPTIC-2L

Official Title

A Randomized, Open-label Study of Ponatinib Versus Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Terminated

Why Stopped

The study was stopped due to operational feasibility and not due to any safety concerns

Study Start Date

December 31, 2015 (Actual)

Primary Completion Date

October 29, 2020 (Actual)

Study Completion Date

January 20, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ariad Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to compare the efficacy and safety of 2 starting doses of ponatinib compared to nilotinib in participants with imatinib-resistant chronic myeloid leukemia (CML) in chronic phase (CP).

Detailed Description

This is a multi-center, randomized study to demonstrate the efficacy and safety of 2 starting doses of ponatinib as a treatment for CP-CML compared to nilotinib. Eligible participants must have chronic phase chronic myeloid leukemia (CP-CML), be resistant to first-line imatinib treatment and have received no other tyrosine kinase inhibitors (TKIs).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Phase Chronic Myeloid Leukemia

Keywords

CML, CP-CML, Leukemia, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms by Histologic Type, Neoplasms, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

44 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort A: Ponatinib 30 mg

Arm Type

Experimental

Arm Description

Arm Title

Cohort B: Ponatinib 15 mg

Arm Type

Experimental

Arm Description

Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 45 months.

Arm Title

Cohort C: Nilotinib 400 mg

Arm Type

Active Comparator

Arm Description

Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.

Intervention Type

Drug

Intervention Name(s)

Ponatinib 30 mg QD

Other Intervention Name(s)

Iclusig, AP24534

Intervention Description

Ponatinib 30 mg, taken orally once daily.

Intervention Type

Drug

Intervention Name(s)

Ponatinib 15 mg QD

Other Intervention Name(s)

Iclusig, AP24534

Intervention Description

Ponatinib 15 mg, taken orally once daily.

Intervention Type

Drug

Intervention Name(s)

Nilotinib 400 mg BID

Other Intervention Name(s)

Tasigna, AMN107

Intervention Description

Nilotinib 400 mg, taken orally twice daily.

Primary Outcome Measure Information:

Title

Percentage of Participants With Major Molecular Response (MMR)

Description

Time Frame

Up to 12 months

Secondary Outcome Measure Information:

Title

Percentage of Participants With Major Cytogenetic Response (MCyR)

Description

Time Frame

Up to 12 months

Title

Percentage of Participants With Complete Cytogenetic Response (CCyR)

Description

Time Frame

Up to 12 months

Title

Percentage of Participants With Molecular Response (MR)

Description

Time Frame

From Month 3 to every 3 months up to 48 months

Title

Percentage of Participants With MR1

Description

MR1 was defined as the percentage of participants achieving a ratio of ≤10% BCR ABL to ABL transcripts on the international scale at 3 months.

Time Frame

Month 3

Title

Percentage of Participants With Treatment Emergent Arterial Occlusive Events (TE-AOEs), Treatment Emergent Venous Thromboembolic Events (TE-VTE), Adverse Events (AEs), and Serious AEs (SAEs)

Description

Time Frame

From first dose up to 30 days post last dose (Up to approximately 46 months)

Title

Time to Response

Description

Time to MMR defined as the interval between the randomization date and the first date at which the criteria for response was met. MMR was defined as <=0.1% BCR-ABL.

Time Frame

Up to approximately 60 months

Title

Duration of Response

Description

Time Frame

Up to approximately 60 months

Title

Progression-free Survival (PFS)

Description

Time Frame

Up to end of study (approximately 60 months)

Title

Overall Survival

Description

Overall survival (OS) defined as the interval between the first dose date of study treatment and date of death due to any cause, censored at the last contact date to be alive.

Time Frame

Up to end of study (approximately 60 months)

Title

Percentage of Participants Who Achieved/Maintained Complete Hematologic Response (CHR)

Description

Time Frame

3 months after the first dose of study treatment

Title

Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption

Description

Time Frame

From first dose up to end of treatment (Up to approximately 45 months)

Title

Percentage of Participants With Progression to Accelerated Phase (AP) or Blast Phase (BP)-CML

Description

Time Frame

Up to end of study (Up to approximately 60 months)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Have CP-CML and are resistant to first-line imatinib treatment. Be male or female ≥18 years old. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Have adequate renal function as defined by the following criterion: • Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution. Have adequate hepatic function as defined by all of the following criteria: Total serum bilirubin ≤1.5 × ULN, unless due to Gilbert's syndrome Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present. Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤1.5 × ULN. Exclusion Criteria: Have previously been treated with any approved or investigational TKIs other than imatinib or treated with imatinib within 14 days prior to receiving study drug. Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy. Underwent autologous or allogeneic stem cell transplant. Are in CCyR or MMR. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (TIA) Any history of peripheral vascular infarction, including visceral infarction Any history of a revascularization procedure, including vascular surgery or the placement of a stent History of venous thromboembolism, including deep venous thrombosis, superficial venous thrombosis, or pulmonary embolism, within 6 months prior to enrollment Congestive heart failure (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than 45% or less than the institutional lower limit of normal (whichever is higher) within 6 months prior to enrollment.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

Facility Name

Cliniques Universitaire Saint-Luc (Site 058)

City

Bruxelles

ZIP/Postal Code

1200

Country

Belgium

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD Sharing 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.

IPD Sharing URL

https://vivli.org/ourmember/takeda/

Learn more about this trial

A Study Comparing Ponatinib and Nilotinib in Participants With Chronic Myeloid Leukemia

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