The primary objective for this study is as follows:Within the TP53 wild-type populationTo compare overall survival (OS) in patients with relapsed or refractory AML who havebeen randomized to idasanutlin in combination with cytarabine versus those…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The efficacy outcome measures for this study are:
* Overall survival (OS)
* Event-free survival (EFS)
* Leukemia-free survival (LFS)
* Complete remission (CR)
* Complete remission with incomplete platelet recovery (CRp)
* Complete remission with incomplete blood count recovery (CRi)
* Overall remission rate (ORR) (CR, CRp, and CRi)
* Proportion of allogeneic HSCT following response
In this study CR and CRp will need to be confirmed for the purpose of the
interim
analysis. Confirmed CR is defined as CR, CRp with a duration of at least 28
days after
hematologic malignancy response assessment (HMRA) at the end of Cycle 1. For all
patients in remission not proceeding to Cycle 2 an additional HMRA is scheduled
30 (±3)
days following End-of-Cycle 1 HMRA. In case a patient proceeds directly to HSCT
in
aplasia after Cycle 1, or prior to HMRA, this will be considered confirmed CR
unless
HSCT was clearly performed in disease progression/relapse.
Secondary outcome
Safety Outcome Measures
The safety outcome measures for this study are:
* Incidence and severity of adverse events and serious adverse events
* Incidence of clinically significant laboratory abnormalities
* ECGs
* Vital signs
* 30- and 60-day mortality rates
Pharmacodynamic/Biomarker Outcome Measures
The pharmacodynamic/biomarker outcome measures for this study are:
* p53 mutation analysis by next generation sequencing
* Serum MIC-1 profile (raw and/or adjusted from baseline as percentage of
change)
* MDM2 expression by qRT-PCR and flow cytometry as well as gene signatures by
qRT-PCR and/or RNA sequencing
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are:
* Apparent clearance (CL/F) and apparent volume of distribution (Vd/F) as well
as Cmax, steady-state concentration at the end of a dosing interval (i.e., just
prior to next drug administration [Ctrough]), area under the concentration*time
curve during one dosing interval (AUC0-*), AUC24h, and t1/2 of idasanutlin (and
M4 metabolite RO6802287)
* Total clearance (CL) and volume of distribution (Vd) of cytarabine
* Effect of idasanutlin on cytarabine PK
* Effect of cytarabine on idasanutlin PK
Patient-Reported Outcome Measures
The Patient-Reported Outcome (PRO) measures for this study are:
* European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire Core 30 (EORTC QLQ-C30)
* EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire
Background summary
The yearly incidence of acute myeloblastic leukaemia (AML) in European adults
is five to eight cases per 100 000 individuals with a steep increase in the
population aged over 70 years where the incidence reaches 15*25/100 000 per
annum (Fey 2013).
Approximately 20,000 patients will be diagnosed with AML with greater than
10,000 AML patient deaths in the United States during 2015 (American Cancer
Society 2015). By intensive initial treatment of acute myeloid leukemia (AML),
using cytarabine and anthracycline*based chemotherapy induction regimens,
complete remission (CR) proportions ranging from 50% to 80% can be achieved.
Nonetheless, the majority of
responding patients under the age of 60 relapse (60%*70%), and results are
poorer in older patients, with fewer than 20% of elderly patients being
long-term survivors (Burnett et al. 2011).
Prognostic factors for AML include age, white blood cell count, percentage of
CD34-positive blasts, cytogenetic and molecular risk factors, and secondary or
therapy-related AML. Improvements have been made in prognostic
subclassification of patients*including those with normal cytogenetics*by
testing for molecular abnormalities (i.e., FLT3, NPM1, CEBPalpha, MLL, WT1, and
EVI1) to allow early identification of patients at high risk of relapse who
should be treated with more intensive therapies (i.e. hematopoietic stem cell
transplant (HSCT), or for whom
experimental therapies are warranted. Patients who do not respond to standard
therapy or who relapse within a year of initial treatment have median survival
measured in months (Breems et al. 2005). No standard regimen exists for the
treatment of patients with relapsed or refractory AML, particularly in patients
with a remission duration of less than 1 year in response to their initial
induction regimen. These patients are
candidates for novel therapeutic interventions with the goal of disease
remission, making potentially curative transplant options available for
appropriate patients (Forman 2005). This will be the population studied in this
clinical trial.
Study objective
The primary objective for this study is as follows:
Within the TP53 wild-type population
To compare overall survival (OS) in patients with relapsed or refractory AML
who have
been randomized to idasanutlin in combination with cytarabine versus those who
have
been randomized to cytarabine and placebo
For secundairy and exploratory objectives please see protocol paragraph 2.2 and
2.3
Study design
This is a Phase III multicenter, double-blind, randomized, placebo-controlled
study of idasanutlin in combination with cytarabine compared with cytarabine
and placebo.
A total of 440 patients with AML who have relapsed following, or are refractory
to cytarabine*containing standard induction chemotherapy after at least 1 and
no more than 2 prior cytarabine*containing induction chemotherapy regimen(s)
are planned to be enrolled. Relapsed patients are defined as patients with
first or second relapse; however patients who are young and had had a good
response to initial therapy (i.e. age < 60 years with first CR (CR1) duration >
1 year) are excluded. Refractory patients are defined as patients with
persistent leukemia after 1 or 2 induction cycles, or patients with CR1
duration of < 90 days. Patients may have received prior HSCT in remission. Note
that patients with prior allogenic HSCT within 90 days prior to randomization
will not be eligible for this study. The TP53 wild-type population will consist
of patients with wild-type TP53, established centrally.
Intervention
The patient receives additional to the standard treatment on the first 5 days
of the cycle two times daily an oral dose of Idasanutlin / placebo. The
patients are asked to fill out two QoL questionnaires multiple times per cycle
using an electronic device. After treatment, the patient will return for a
follow-up visit and blood sample will be collected monthly and bone marrow
aspirate will be taken three monthly to assess the status of the leukemia.
Study burden and risks
The number of times the patient will visit the hospital, the number of blood
tests and other study-related activities is dependent on the duration of a
cycle and the number of cycles that the patient will stay in the study. Study
Specific actions include: ICF, QoL questionnaires, oral dose of Idasanutlin /
placebo. In addition, the patient can give separate consent to blood sampling
for RCR
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Listed location countries
Age
Inclusion criteria
- Age * 18 years,
- Documented/confirmed 1st/2nd refractory/relapsed AML using World Health
Organization classification, except acute promyelocytic leukemia and first
relapsed AML patients with a CR1 duration of >1 year AND age <60 years. ,
- No more than 2 prior induction regimens (excl. prior HSCT) in their first
line treatment and one must have included cytarabine with an anthracycline (or
anthracenedione).,
- Eastern Cooperative Oncology Group performance status of 0 * 2
- Adequate hepatic function assessed by the following: Serum total bilirubin *
1.5 x institutional upper limit of normal (ULN), unless resulting from
hemolysis, Gilbert*s syndrome, or liver infiltration with leukemia. AST/ALT * 3
x institutional ULN (or * 5 x upper limit of institutional laboratory reference
range if liver infiltration with leukemia)
- Adequate renal function assessed by serum creatinine within reference
laboratory ranges OR creatinine clearance (by Cockcroft Gault formula) * 50
mL/min.,
- WBC count at randomization of *50.000/mm3
Note: When treatment is not started immediately upon randomization, the WBC
count at the start of induction therapy (C1) must remain at *50.000/mm3. The
use of hydroxyurea (HU) or leukapheresis to meet eligibility is allowed. HU or
leukapheresis must be discontinued at least 24 hours prior to the initiation of
study medication.
- For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use two adequate methods of contraception,
including at least one method with a failure rate of < 1% per year, during the
treatment period and for up to 6 months after the last dose of study drug.
Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, and established, proper use of
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine
devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception. Barrier methods must always be supplemented with the use of a
spermicide., - For men unless permanently sterile by bilateral orchidectomy:
agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures and agreement to refrain from donating sperm, as defined
below:
With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during the treatment period and for up to
6 months after the last dose of study drug. Men must refrain from donating
sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient., - Ability to understand and willingness to sign a written informed
consent form and comply with all study requirements including completion of PRO
measures.
Exclusion criteria
- First relapsed patients with CR1 duration of >1 year AND age <60 years,
- Patients with prior documented AHD including the following: myelodysplastic
syndrome, myeloproliferative disease (i.e., chronic myelomonocytic leukemia,
polycythemia vera, primary myelofibrosis, and essential thrombocythemia), and
aplastic anemia,
- AML secondary to any prior chemotherapy unrelated to leukemia,
- Patients who are either refractory to or have relapsed within 90 days of
receiving a regimen containing a cumulative dose of * 18 g/m2 cytarabine,
- Patients who have received allogeneic HSCT within 90 days prior to
randomization. HSCT should have been performed in remission and not used for
salvage (patients who have received autologous HSCT as consolidation in CR1 are
eligible).,
- Patients who have received immunosuppressive therapy for graft versus host
disease (GvHD) or for engraftment syndrome after autologous stem cell
transplantation within 2 weeks prior to randomization
- Prior treatment with a Murine Double Minute 2 (MDM2) antagonist,
- Patients with clinically relevant QTc prolongation (QTcF> 480 ms), a family
history of long QT syndrome, or who are currently receiving treatment with
medications that are known to prolong the QT interval,
- Patients receiving any other investigational or commercial agents or
therapies administered with the intention to treat their malignancy within 30
days (or 5 half-lives) from first receipt of study drug. Note: The exception is
HU or leukapheresis in patients who need to continue this therapy to maintain a
WBC count * 50,000/mm3. HU or leukapheresis must be discontinued at least 24
hours prior to the initiation of study medication,
- Patients with acute toxicities from any prior anti-leukemia therapy which
have not resolved to Grade * 2 per National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.03.,
- Patients with a history of other malignancy within 5 years prior to screening
except for malignancy that has been in remission without treatment for at least
2 years prior to randomization,
- Patients unable to temporarily interrupt treatment with moderate to strong
CYP2C8 inducers and inhibitors (including gemfibrozil, which is also an
inhibitor of UGT1A3), CYP2C8 or OATP1B1/3 substrates, or strong CYP3A4 inducers
as defined inTable 3, Table 4, and Table 5 of the protocol during the treatment
phase. These agents must be discontinued 7*14 days prior to the start of study
medication.,
- Patients unable to temporarily interrupt treatment with oral or parenteral
anticoagulants/anti-platelet agents (e.g., warfarin, chronic daily treatment
with aspirin [> 325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban)
during the treatment phase. These agents must be discontinued 7 days (or 5
half-lives) prior to the start of study medication.
Note: treatment with or switch to low molecular weight heparin (LMWH) or
unfractionated heparin (UFH) is allowed, according to local practice. However,
platelet levels need to be closely monitored in these patients (see protocol).
- Patients with history of systemic hypersensitivity reactions * grade 2
attributed to cytarabine or components of the formulated product,
- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study, impair the
ability of the investigator to evaluate the patient, or impair the patient*s
ability to complete the study (for examples see protocol),
- Infection considered by the investigator to be clinically uncontrolled or of
unacceptable risk to the patient upon the induction of neutropenia, that is
patients who are or should be on anti-microbial agents for treatment of active
infection (for examples see protocol),
- Patients with a history of active or chronic infectious hepatitis unless
serology demonstrates clearance of infection, - Patients who have a history of
clinically significant liver cirrhosis.,
- Patients with clinically significant electrolyte abnormalities such as
hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and
hypermagnesemia of Grade > 1 per NCI CTCAE v4.03. Treatment for correction of
above electrolyte imbalances is permitted during screening to meet eligibility,
- Patients with extramedullary AML with no evidence of systemic involvement,
- Patients with active CNS leukemia,
- Pregnant or breastfeeding patients., - HIV-positive patients,
- Patients who might refuse to receive blood products and/or have a
hypersensitivity to blood products.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003065-15-NL |
| ClinicalTrials.gov | NCT02545283 |
| CCMO | NL54789.068.15 |