This study will evaluate the safety, tolerability, and pharmacokinetics of idasanutlin as a single agent and the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin in combination with either chemotherapy or venetoclax in…
ID
Source
Brief title
Condition
- Other condition
- Leukaemias
Synonym
Health condition
Solid Tumors / Neuroblastoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy objective for this study (Study Parts 1b, 2 and 3) is to
evaluate the anti cancer activity of idasanutlin in combination with
chemotherapy or venetoclax on the basis of the following endpoints:
Neuroblastoma
- Objective response rate (ORR), defined as the proportion of patients with
complete response or partial response (PR) at any time during study treatment,
on two consecutive occasions more or equal to 4 weeks apart, as determined by
the investigator according to INRC for patients with neuroblastoma.
Primary efficacy analysis will be conducted on patients with TP53 wild-type
(WT) tumors in Study Parts 1b, 2 and 3.
Leukemia
- Complete remission rate (CRR), defined as the proportion of patients with
morphologic complete remission, complete remission with incomplete blood count
recovery (CRi) or complete remission with incomplete platelet count recovery
(CRp), within 2 cycles of study treatment
- For patients with acute lymphocytic leukemia (ALL): minimal residual disease
(MRD)-negative rate, defined as the proportion of patients with ALL who have an
MRD value < 0.01%, as measured by next generation sequencing (NGS), within 2
cycles of study treatment
Primary efficacy analyses will be conducted on patients with TP53 WT tumors in
Study Parts 2 and 3.
Secondary outcome
The secondary efficacy objective for this study (Study Parts 1, 2, and 3) is to
evaluate the anti cancer activity of idasanutlin as single agent, in
combination with chemotherapy, and in combination with venetoclax (in patients
with TP53 WT tumors, as well as in all patients regardless of mutation status)
on the basis of the following endpoints:
Solid tumors (including Neuroblastoma)
- Clinical benefit rate (CBR), defined as the proportion of patients achieving
confirmed complete response, PR, or SD on two consecutive occasions more or
equal to 4 weeks apart during the total study period
- Duration of objective response (DOR), defined as the time from the first
tumor assessment that supports a patient*s objective response to the time of
disease progression or death from any cause (whichever occurs first), as
determined by the investigator using INRC for patients with neuroblastoma or
RECIST v1.1 for patients with other solid tumors
- Progression-free survival (PFS), defined as the time from initiation of study
drug to the first documented occurrence of disease progression or death from
any cause (whichever occurs first), as determined by the investigator using
INRC for patients with neuroblastoma and RECIST v1.1 for patients with other
solid tumors
- Overall survival (OS), defined as the time from initiation of study drug to
death from any cause
- ORR of efficacy-evaluable population irrespective of TP53 mutation status
Leukemia
- Number of patients receiving transplant after study treatment
- DOR, defined as the time from the first tumor assessment that supports the
patient's objective response (CR, CRp, CRi) to the time of relapse, or death
from any cause, whichever occurs first
- EFS, defined as the time from initiation of study drug to the first
documented occurrence of M3 marrow after Cycle 1, failure to achieve CR/CRp/CRi
after Cycle 2, disease progression, relapse subsequent to achieving CR/CRp/CRi,
or death from any cause, whichever occurs first.
- OS, defined as the time from initiation of study drug to death from any cause
- CRR of efficacy-evaluable population irrespective of TP53 mutation status
- For patients with acute myeloid leukemia (AML): MRD-negative rate, defined
as the proportion of patients with AML who are MRD negative within 2 cycles of
study treatment
Background summary
See protocol version 2 (19Jul2019), section 1 " background", pages 30-41
Study objective
This study will evaluate the safety, tolerability, and pharmacokinetics of
idasanutlin as a single agent and the safety, tolerability, pharmacokinetics,
and preliminary efficacy of idasanutlin in combination with either chemotherapy
or venetoclax in children and young adults with acute leukemias or solid tumors
that are recurrent or refractory to standard therapy.
In this protocol, "study treatment" refers to the single agent or combination
of treatments assigned to patients as part of this study (i.e., idasanutlin
with or without chemotherapy or venetoclax). Specific objectives and
corresponding endpoints for the study are outlined below.
Safety Objectives
The safety objectives for this study are to evaluate the safety and
tolerability of idasanutlin as a single agent, in combination with
chemotherapy, and in combination with venetoclax; to determine the maximum
tolerated dose (MTD)/maximum administered dose (MAD) of idasanutlin
administered as a single agent; and to define the recommended Phase 2 dose
(RP2D) of idasanutlin in combination with either chemotherapy or venetoclax on
the basis of the following endpoints:
- Incidence and severity of adverse events with severity determined according
to the National Cancer Institute Common Terminology Criteria for Adverse
Events, Version 5 (NCI CTCAE v5.0)
- Changes from baseline in physical findings
- Changes from baseline in targeted clinical laboratory test results and ECG
parameters
- Incidence of dose-limiting toxicities (DLTs) assessed during the first cycle
of study treatment of single agent idasanutlin and again with idasanutlin in
combination with chemotherapy or venetoclax
The exploratory safety objective for this study is to evaluate the impact of
idasanutlin as a single agent and in combination with chemotherapy and
venetoclax on growth and development on the basis of the following endpoints:
- Changes from baseline in growth patterns (relative to age-specific standards
for height and weight)
- Changes from baseline in development patterns (relative to onset of menarche
[for females] and pubertal changes)
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:
- To characterize the PK profile of idasanutlin as a single agent and in
combination with chemotherapy or venetoclax on the basis of the following
endpoints:
- Plasma concentration of idasanutlin (and M4 metabolite
RO6802287, where relevant) as a single agent at specified timepoints
- Plasma concentration of idasanutlin in combination with
chemotherapy or venetoclax at specified timepoints
- To characterize the PK profile of venetoclax in combination with idasanutlin
on the basis of the following endpoint:
- Plasma concentration of venetoclax at specified timepoints
Exploratory Biomarker Objectives
The exploratory biomarker objective for this study is to identify biomarkers
that are predictive of response to idasanutlin as a single agent or in
combination with chemotherapy or venetoclax; are early surrogates of efficacy;
are associated with progression to a more severe disease state (i.e.,
prognostic biomarkers); are associated with acquired resistance to idasanutlin
as a single agent or in combination with chemotherapy or venetoclax; are
associated with susceptibility to developing adverse events or can lead to
improved adverse event monitoring or investigation (i.e., safety biomarkers);
can provide evidence of idasanutlin activity (i.e., pharmacodynamic biomarkers)
as a single agent or in combination with chemotherapy or venetoclax; or can
increase the knowledge and understanding of disease biology and drug safety, on
the basis of the following endpoints:
- Relationship between biomarkers identified in blood versus tissue and
efficacy, safety, PK, immunogenicity, or other biomarker endpoints
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate
the acceptability and palatability of idasanutlin on the basis of the following
endpoint:
- Acceptability Survey scores at Cycle 1, Day 5
We are convinced that this research can have a therapeutic effect on patients.
For a detailed explanation, we refer you to the enclosed documents and the
accompanying letter.
Study design
Description of Study
The study is divided into three parts:
Study Part 1:
- Part 1a: Dose escalation to assess safety, tolerability, and pharmacokinetics
of
idasanutlin as a single-agent treatment in the pediatric population with
relapsed or
refractory solid-tumors; to identify the single-agent MTD/MAD; and to
characterize
DLTs. Patients in dose escalation after one cycle will either continue
single-agent
idasanutlin or start early combination of idasanutlin with chemotherapy (for
precise
rules, see protocol).
- Part 1b: Following single-agent MTD/MAD identification, separate safety
run-in cohorts
will be conducted in neuroblastoma with newly enrolled patients to identify the
RP2Ds
of idasanutlin in combination with cyclophosphamide and topotecan and in
combination
with venetoclax. These cohorts will also provide early efficacy assessments of
these
combinations in the patients with TP53 WT tumors treated at the RP2Ds.
Additional
safety run-in cohorts will be conducted in AML to identify the RP2D of
idasanutlin
in combination with fludarabine and high-dose cytarabine (FLA) and in AML and
ALL to identify the RP2D of idasanutlin in combination with venetoclax in
patients
with leukemia.
- Study Part 2: In cohorts that pass the safety and efficacy criteria for Part
1b (Gate 1b),
evaluation of safety and efficacy of idasanutlin in combination with
chemotherapy or
venetoclax will be continued in neuroblastoma, AML, and/or ALL at the RP2D(s)
for the
combinations.
- Study Part 3: Potential expansion of idasanutlin combination cohorts in
neuroblastoma,
AML, and/or ALL meeting the pre-defined efficacy criteria for expansion (Gate
2), also
taking into account practical considerations (e.g., enrollment feasibility),
nonclinical findings,
biomarker analysis, safety profiles, and any other relevant information.
In Study Part 1a, only patients < 18 years of age will be enrolled. In Study
Parts 1b, 2, and 3,
pediatric and young adult patients with neuroblastoma or acute leukemias (age:
birth to
< 30 years) will be enrolled.
Idasanutlin will be administered orally to patients once daily for Days 1-5 of
each cycle,
followed by 23 days of rest, for a total cycle duration of 28 days. All
patients will be closely
monitored for adverse events (regardless of relationship to study drug)
throughout the study and
for at least 30 days after the last dose of study treatment or until initiation
of a new anti-cancer
therapy, whichever comes first.
Patients will be enrolled regardless of their TP53 mutation status, as not all
TP53 mutations
may be inactivating; therefore, responses may still be observed in some
patients with TP53
mutations. A pre-idasanutlin tumor biopsy of current disease within 6 months
of screening and
after the last anti-cancer therapy is required for patients with solid tumors
unless approved by
the Medical Monitor. A bone marrow aspirate (BMA) specimen is required within
the
screening period for patients with leukemia. Samples will be analyzed for TP53
mutation status
by centralized molecular testing. If available, sites must also report any
local molecular testing
results for TP53 mutation status in the eCRF.
An internal monitoring committee and external scientific oversight committee
(IMC/SOC) will be
established for safety monitoring at pre-defined study milestones and
approximately every
6 months.
Study Part 1a -Single-Agent Dose Escalation
The study will begin with a dose-escalation phase with idasanutlin in patients
with solid tumors
using the modified continual reassessment method of escalation with overdose
control
(mCRM-EWOC) to identify the single-agent MTD/MAD. Approximately 9*24
DLT-evaluable
patients are anticipated to be enrolled in this phase. Based on
physiologically-based
pharmacokinetic (PBPK)-predicted exposures in children, the starting dose in
this escalation
cohort is defined as 2 mg/kg/day (dose level 1). Dose-level escalation or
de-escalation (if
required) will be decided following review of PK and safety data.
The single-agent DLT window will be 28 days (one cycle duration) and until ANC
>= 0.75 x 10 9/L
and platelet count >= 75 x 10 9/L are achieved. Following the first cycle,
patients will undergo
response and DLT assessment. Any delay > 14 days in treatment due to delayed
platelet
recovery will also be considered a DLT; therefore, DLT assessment may extend
until platelet
count recovery.
- Patients who do not experience a DLT or progressive disease will have the
option (with
investigator approval) to continue single-agent idasanutlin or start
combination therapy with
cyclophosphamide/topotecan with a dose reduction in idasanutlin of 20%.
- Patients who do not experience a DLT but do experience progressive disease
may continue
idasanutlin (with a 20% dose reduction) in combination with
cyclophosphamide/topotecan
with investigator and Medical Monitor approval, but will not be permitted to
continue
idasanutlin monotherapy.
- Patients who experience a DLT but have CR, PR, or SD will have the option to
continue
single-agent treatment (dose reduced by 20%) upon adequate recovery from
toxicities and
depending on the nature of the specific toxicity, as jointly judged by
investigator and the
Medical Monitor.
- Patients who experience a DLT and progressive disease will permanently
discontinue study
therapy.
Patients will start subsequent cycles of therapy after Day 28 and when ANC >=
0.75 x 10 9/L and
platelet count >= 75 x 10 9/L are achieved. Patients who remain on study
therapy (single agent or
combination) will continue until the occurrence of disease progression as
determined by the
investigator, death, unacceptable toxicity, or patient/guardian or investigator
decision to
discontinue treatment.
Study Part 1b - Combination Therapy Safety Run-In
Once the idasanutlin single-agent MTD/MAD has been identified, a safety run-in
phase with
newly enrolled pediatric patients will be conducted to identify RP2Ds for
idasanutlin in
combination with chemotherapy or venetoclax in separate neuroblastoma, AML, and
ALL
combination cohorts. The safety run-in phase will start at a maximum of 80% of
the idasanutlin
MTD/MAD identified in the dose-escalation phase, combined with the following
regimens in the
listed diseases:
- Idasanutlin + chemotherapy:
- Neuroblastoma: cyclophosphamide + topotecan
- AML: fludarabine + cytarabine
- Idasanutlin + venetoclax:
- Neuroblastoma
- ALL and AML, with different DLT rules for hematologic toxicity
Assignment of patients to either the chemotherapy or venetoclax cohort will be
at the
investigator's discretion and in accordance to the availability of open slots
for enrollment.
The DLT criteria (disease-type dependent) are modified from those used in the
single-agent
dose escalation cohort in order to determine more appropriately the RP2D in the
setting of
combinations with agents that have anticipated effects on bone marrow
suppression.
Dose-escalation decisions will be dependent on pharmacokinetics and totality of
data. Only the
idasanutlin dose will be escalated, while chemotherapies or venetoclax doses
will not be
escalated. However, idasanutlin, chemotherapy, and/or venetoclax doses may be
de-escalated
based on the totality of the data as determined by the Medical Monitor.
For each combination cohort, the first patient at the first dose level must
complete at least
5 days of treatment without a DLT before subsequent patients can be treated at
the same dose
level. Dose modifications will be conducted according to design similar to a
3+3 design, except
with additional restrictions: a maximum of one higher dose level from the
starting dose-level
cohort, or one lower dose-level cohorts of idasanutlin, will be permitted. If
one dose level below
the starting dose of idasanutlin is considered intolerable, the combination
will be discontinued.
As the safety profile of idasanutlin may differ among c
Intervention
The investigational medicinal products (IMPs) for this study are idasanutlin,
venetoclax, cyclophosphamide, topotecan, fludarabine, and cytarabine.
Test Product (Investigational Drug)
Idasanutlin will be supplied as 5-mg and 20-mg dispersible tablets. The
dispersible tablets can either be swallowed or used to prepare a suspension (ad
hoc) for patients not able to swallow tablets. Idasanutlin will be
administered as an oral medication once daily on Days 1-5 of a 28 day cycle.
The starting daily dose of idasanutlin in the dose-escalation phase of the
study will be 2 mg/kg/day and will be modified according to the protocol.
Venetoclax (GDC 0199/ABT 0199) will be supplied as oral film coated tablets of
10 mg, 50 mg, and 100 mg strength. Venetoclax will also be provided as 2.5-mg,
10-mg, and 25-mg tablets for oral suspension for patients not able to swallow
tablets.
Venetoclax (in combination with idasanutlin) will be administered at the adult
dose equivalent (adjusted by body weight) of 400 mg in patients with
neuroblastoma and the adult dose equivalent of 600 mg in patients with leukemia
once daily on days 1-28 of a 28 day cycle. For patients with solid tumors,
venetoclax will ramp-up to the target dose over 2 days (200 mg equivalent Day 1
to 400 mg equivalent Day 2). Patients with neuroblastoma receiving venetoclax
should be hospitalized during the ramp-up phase until the target dose has been
administered. For patients with leukemia, venetoclax will ramp-up to the
target dose over 3 days (150 mg equivalent Day 1; 300 mg equivalent Day 2; 600
mg equivalent Day 3). If lower doses of venetoclax are required, intermediate
doses for the ramp up will be proportionally adapted based on the duration of
ramp-up period (2 or 3 days), the final dose to be achieved, and the available
formulation dose strength. For guidance on dose reductions in case of
co-administration with CYP3A4 or P-gp, refer to protocol.
For patients assigned to arms combining idasanutlin with chemotherapy,
chemotherapy should be administered at the doses prescribed below. Infusion
duration, prophylactic medications, and monitoring guidelines should be managed
in accordance with institutional standard unless specified in the protocol.
Neuroblastoma
Cyclophosphamide and topotecan will be administered once daily on Days 1-5 of
each 28-day cycle at the following doses:
- Cyclophosphamide 250 mg/m2 as an intravenous (IV) infusion over 1 hour
- Topotecan 0.75 mg/m2 as an IV infusion over 1 hour
Acute Myeloid Leukemia
FLA (fludarabine and high-dose cytarabine) chemotherapy will be administered
during each 28 day combination treatment cycle as per the following regimen:
- Fludarabine 30 mg/m2 IV Days 1 to 5 over 30 minutes
- Cytarabine 2000 mg/m2 IV Days 1 to 5 over 4 hours
Note: Cytarabine infusion is administered 4 hours after the start of the
fludarabine infusion.
The non-IMPs in the study include the prophylactic medications (anti-diarrheal
agents, antibiotics, anti-fungal agents, uric acid reducing agents, anti-PCP
therapy, and 5-HT3-receptor antagonists) and the intrathecal chemotherapy
agents (intrathecal cytarabine, methotrexate, and hydrocortisone).
Study burden and risks
An overview of the risks can be found in the patient information forms added to
this submission.
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Listed location countries
Age
Inclusion criteria
Signed informed consent before any study-specific screening procedures are
conducted, and age-appropriate assent when considered appropriate according to
local, regional, or national guidelines
Age < 18 years at the time of signing informed consent for Part 1a, < 30 years
at time of signing informed consent for pats 1b, 2 and 3; Note: The Sponsor may
decide to stop enrollment of patients who are at least 18 years at any time
during the study to ensure adequate enrollment of patients who are younger than
18 years.
Study Part 1a (single-agent therapy dose escalation): histologically confirmed
diagnosis of neuroblastoma or other solid tumor that has progressed or recurred
despite standard therapy, and for which there is no therapy proven to prolong
survival with an acceptable quality of life
Study Part 1b (safety run-in), Study Part 2, and Study Part 3: histologically
confirmed diagnosis of neuroblastoma, AML, or precursor-B ALL that has
progressed or recurred despite, or is refractory to, standard therapy
Adequate performance status
Adequate end-organ function defined by the following laboratory results
obtained within 28 days prior to initiation of study drug.
For females of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraception, agreement to refrain from
donating eggs.
For males: agreement to remain abstinent (refrain from heterosexual
intercourse) or use a condom, and agreement to refrain from donating sperm.
Additional Inclusion Criteria for Patients with Solid Tumors (including
Neuroblastoma)
At least one evaluable or measurable radiological site of disease as defined by
standard criteria for the patient*s tumor type (e.g., INRC), or measurable bone
marrow disease by morphology
Adequate end-organ hematologic function
Tumor tissue from relapsed disease, obtained subsequent to last anti cancer
therapy regimen administered and obtained within 6 months prior to study
enrollment, or willingness to undergo a core or excisional biopsy sample
collection prior to enrollment
- Patients must submit a tissue block or 15 slides containing unstained,
freshly cut, serial sections available for submission.
- Fine needle aspirations, brush biopsies, bone metastasis samples, and lavage
samples are not acceptable.
- Patients with less than 15 slides available, or whose tumor tissue does not
otherwise meet criteria above, may be eligible for study entry after Medical
Monitor approval has been obtained. See protocol for detailed tissue
requirements.
Life expectancy of at least 12 weeks, in the investigator's judgment
Additional Inclusion Criteria for Patients with Leukemia
Bone marrow with at least 5% lymphoblasts by morphologic assessment at screening
Available bone marrow aspirate or biopsy from screening
Exclusion criteria
Primary CNS tumors
Symptomatic CNS metastases that result in a neurologically unstable clinical
state or require increasing doses of corticosteroids or local CNS-directed
therapy to control the CNS disease
CNS3 leukemia (total nucleated cell count at least 5/*L with blasts on
cytocentrifuge in an atraumatic lumbar puncture, or clinical signs of CNS
leukemia including cranial nerve palsy)
Acute promyelocytic leukemia
White blood cell count more than 50 * 109/L
Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any
known bone marrow failure predisposition syndrome (including, but not limited
to, Fanconi anemia or dyskeratosis congenita)
Burkitt-type acute lymphoblastic leukemia (mature B-cell)
T-cell lymphoblastic leukemia
Prior treatment with an MDM2 antagonist
Prior treatment with venetoclax (if potential for enrollment in a venetoclax
arm)
Infection considered by the investigator to be clinically uncontrolled or of
unacceptable risk to the patient upon induction of neutropenia, including
patients who are, or should be, on antimicrobial agents for the treatment of
active infection.
Pregnant or breastfeeding, or intending to become pregnant during the study
Females of childbearing potential must have a negative serum pregnancy test
result within 1 week prior to initiation of study drug.
Active GI disease (e.g., gut graft-versus-host disease, Crohn's disease,
ulcerative colitis) or GI conditions that may significantly alter drug
absorption of oral drugs (e.g., uncontrolled vomiting, diarrhea, or
malabsorption syndrome)
Active viral hepatitis or human immunodeficiency virus (HIV) infection
Presence of any CTCAE at least Grade 2 clinically significant treatment-related
toxicity with the exception of alopecia, ototoxicity, peripheral neuropathy and
parameters otherwise permitted in the inclusion criteria (e.g., hematological
criteria)
Clinically relevant QTc prolongation (QTcF more than 450 ms using the
Fridericia correction)
Any uncontrolled medical condition or other identified abnormality that
precludes the patient's safe participation in and completion of the study, as
judged by the investigator
Systemic anticancer therapy within 28 days or 5 half-lives, whichever is
shorter, prior to initiation of study treatment
Treatment with monoclonal antibodies, antibody drug conjugates, or cellular
therapy (e.g., CAR-T cell infusion) for anti-neoplastic intent within 30 days
prior to initiation of study treatment
I-131 MIBG therapy within 6 weeks prior to initiation of study treatment
Myeloablative therapy with autologous or allogeneic hematopoietic stem cell
rescue within 100 days of study treatment initiation
Immunosuppressive therapy for treatment of graft-versus-host disease within 2
weeks of study treatment initiation
Radiotherapy (non-palliative) within 3 weeks prior to study treatment
initiation
Known hypersensitivity to any study drug or component of the formulation that
could potentially be allocated according to tumor type
Received the following within 7 days prior to initiation of study treatment:
- Strong CYP2C8 inhibitors
- CYP2C8 substrates
- OATP1B1/3 substrates
Received strong CYP2C8 and strong CYP3A4 inducers within 14 days prior to the
initiation of study treatment
For patients assigned or randomized to venetoclax arms:
- Strong or moderate CYP3A4 inhibitors or moderate inducers or P-gp inhibitors
within 7 days of study drug initiation
- Grapefruit, grapefruit products, Seville oranges (including marmalade
containing Seville oranges), or starfruit within 3 days prior to the initiation
of study treatment
- Vaccination with a live vaccine less than or equal to 28 days prior to
randomization
Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives
prior to study treatment initiation
Underwent major surgical procedure within 21 days of study treatment
initiation, or anticipate need for major surgical procedure during the course
of the study
Gastrostomy, tumor biopsy, and insertion of central venous access devices are
not generally considered major surgery, but the Medical Monitor should be
notified of these or other minor procedures prior to initiating therapy.
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 | EUCTR2018-004579-11-NL |
| ClinicalTrials.gov | NCT04029688 |
| CCMO | NL71291.041.19 |