A Phase I/II, Multicenter, Open-Label, Multi-Arm Study Evaluating the Safety, Tolerability in Combination with Either Chemotherapy or Venetoclax in the Treatment of Pediatric and Young Adult Patients with Relapsed/Refractory Acute Leukemias or Solid Tumors

Study Description

The purpose of this research is to 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. 

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 espite, or is refractory to, standard therapy.

Adequate performance status:

• Patients < 16 years of age: Lansky ≥ 50%
• Patients ≥ 16 years of age: Karnofsky ≥ 50% 

Adequate 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 × ULN for age (or ≤ 2.5 × ULN if liver infiltrated with leukemia or metastases)
  • AST or ALT ≤ 3 × ULN for age (or ≤ 5 × 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.

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. 

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  Updated 12/13/2019 

Adequate end-organ hematologic function, as specified in the following parameters: 

• Hemoglobin ≥ 8 g/dL (transfusion allowed) 
• Peripheral ANC ≥ 0.75 × 109/L (no G-CSF support for 72 hours) 
• Platelet count ≥ 75 × 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 

• 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 and lavage samples are not acceptable. 
• Patients with < 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 ≥ 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

Patients who meet any of the following criteria will be excluded from study entry:
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 ≥ 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 × 109/L

• Prior cytoreduction with leukapheresis or hydroxyurea (HU) is allowed to meet this criterion. HU must be discontinued at least 24 hours prior to the initiation of study treatment.
• Prior cytoreduction with leukapheresis or hydroxyurea is allowed in patients with a WBC count ≤ 50 × 109/L if the patient is symptomatic from hyperleukocytosis, or if consistent with institutional guidelines.

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

• Requirement may be waived at the investigator's request, with approval of the Medical Monitor, if the patient has recovered from therapeutic toxicity to the degree specified in the protocol.
• Intrathecal chemotherapy per protocol prior to starting study therapy is permissible.

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 CYP3A 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 ≤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.