Study Overview

The study is divided into three parts: Study Part 1:
Dose escalation to assess safety, tolerability, and pharmacokinetics of idasanutlin as a single-agent treatment in the pediatric patients with relapsed or refractory solid-tumor cancer; patients in Part 1 after one cycle of single agent idasanutlin can add chemotherapy agents in combination with idasanutlin.

Following single-agent dose finding phase of the trial, three separate cohorts for neuroblastoma, AML, and ALL will be conducted with newly enrolled pediatric patients to identify the dose of idasanutlin in each combination, with chemotherapy or venetoclax.

Study Part 2:
Evaluation of safety and effectiness of idasanutlin in combination with chemotherapy or venetoclax in pediatric and young adult patients with relapsedrefractory neuroblastoma, AML, and ALL cohorts.

Study Part 3:
Expansion of idasanutlin combination cohorts in neuroblastoma, AML, or ALL 

Study Eligibility

Inclusion Criteria

Patients must meet the following criteria for study entry:

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< 30 years at time of signing informed consent. Patients aged 18-30 years are eligible only for Parts 2 and 3 of the study; the Sponsor may decide to stop enrollment of patients who are ≥ 18 years at any time during the study to ensure adequate enrollment of patients who are < 18 years.

Study Part 1 (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 1 (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:

Patients < 16 years of age: Lansky ≥ 50%

Patients ≥ 16 years of age: Karnofsky≥ 50%

Adequate hematologic and end-organ function defined by the following laboratory results obtained within 28 days prior to initiation of study drug:

Renal and liver function

Creatinine ≤ 1.5 ULN for age; if higher, an estimate GFR based on the Schwartz equation (Schwartz et al. 2017) or as per institutional guidelines must be ≥ 60mL/min/1.73 m2

Bilirubin ≤ 1.5 x ULN for age (or ≤ 2.5 x ULN if liver infiltrated with leukemia or metastases)

AST or ALT ≤ 3 x ULN for age (or ≤ 5 x ULN if liver infiltrated with leukemia or metastases)

Cardiac function

Fractional shortening (FS) ≥ 28% or left ventricular ejection fraction (LVEF) ≥ 50%, as determined by echocardiography or multigated acquisition scan (MUGA) within 28 days prior to initiation of study therapy

Depending on institutional standard, either FS or LVEF is adequate for enrollment if only one value is measured; if both values are measured, then both values must meet the above criteria.

Patients must be able to swallow tablets or liquid

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 hematologic function:

Hemoglobin ≥ 8 g/dL (transfusion allowed)

Peripheral ANC ≥ 0.75 x 109/L (no G-CSF support for 72 hours)

Platelet count ≥ 75 x 109/L (unsupported for 72 hours)

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

Life expectancy ≥ 12 weeks, in the investigator's judgment

Additional Inclusion Criteria for Patients with Leukemia

Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening

Available bone marrow aspirate or biopsy from screening

Exclusion Criteria

Primary central nervous system (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 V ≥ 5/µL 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 > 50 x 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 ≥ 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 > 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 inducers within 14 days prior to the initiation of study treatment

For patients assigned or randomized to venetoclax arms:

Strong or moderate CYP3A inhibitors or inducers 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

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.

Contact

For more information about this study, contact Catherine Redinger at 501-364-4290 (RedingerCatherineL@uams.edu) or Suzy Hall at 501-364-4181 (Hallsf@archildrens.org).