takeda/studies/attachments/PLS_AP24534-15-303-plain-language-summary

Plain Language Summary - English

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CSR Synopsis - English

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).

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

Leukemia

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).

Ponatinib 30 mg QD

Ponatinib 15 mg QD

Nilotinib 400 mg BID

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

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.

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.

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.

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.

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.

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 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 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) 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 (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.

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).

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.

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.

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.

Chronic Phase Chronic Myeloid Leukemia

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).

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).

Cliniques Universitaire Saint-Luc (Site 058)

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.

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.

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.

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.

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.

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 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 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) 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 (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.

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).

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.

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.

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.

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

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Trial Results Summary

Clinical Study Report Synopsis

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Locations

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Status