Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer

Status: Recruiting
Phase:
DFCI Protocol ID: 18-284

This research study is studying a novel drug called ALRN-6924 as a possible treatment for resistant (refractory) solid tumor, brain tumor, lymphoma or leukemia. The drugs involved in this study are: - ALRN-6924 - Cytarabine (for patients with leukemia only)

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

Steven Dubois MD, Dana Farber Cancer Institute

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

Inclusion Criteria:

  -  Age > 1 years and ≤ 21 years at time of enrollment.

  -  Karnofsky performance status ≥ 50% for patients ≥16 years of age and/or Lansky ≥ 50%
     for patients <16 years of age

  -  For Cohorts A and B

       -  Participants must have evaluable or measurable disease.

       -  Must have disease that is relapsed or refractory and for which standard curative
  or palliative measures do not exist or are no longer effective.

       -  For Cohort A, participants must have histologically confirmed non-CNS primary
  solid tumors or lymphoma based upon biopsy or surgery at initial diagnosis and/or
  relapse/progression. The only exception to histologic confirmation is for
  patients with retinoblastoma.

       -  For Cohort B, participants must have one of the following confirmed diagnoses:

    -  Diagnosis of retinoblastoma

    -  Histologic diagnosis of hepatoblastoma and WT TP53

    -  Solid tumor, CNS tumor, or lymphoma with MDM2 amplification or high-copy
       gain and WT TP53

    -  Solid tumor, CNS tumor, or lymphoma with MDMX amplification or high-copy
       gain and WT TP53

    -  Solid tumor or lymphoma with TET2 loss or loss-of-function mutation and WT
       TP53

    -  Testing for MDM2, MDMX, TP53, and TET2 variants must be performed in a
       laboratory certified to return results for clinical purposes in order to be
       used to qualify a patient for Cohort B.

  -  For Cohort C

       -  Participants must have a histologically confirmed diagnosis of relapsed or
  refractory AML, ALL, mixed lineage leukemia, biphenotypic leukemia, or other
  undifferentiated acute leukemia with one of these disease states:

       -  Refractory disease defined as: Persistent disease after at least two induction
  cycles; OR

       -  Relapsed disease defined as: Second or subsequent relapse, or any relapse that is
  refractory to salvage chemotherapy

       -  Subjects in Cohort C must have ≥ 5% blasts (M2 or M3 marrow) definitively
  identified either on a bone marrow aspirate or biopsy sample, as assessed by
  morphology, immunohistochemical studies, flow cytometry, karyotype, cytogenetic
  testing such as fluorescent in situ hybridization (FISH) or other molecular
  studies.

       -  Subjects must have CNS1 or CNS2 disease.

  -  Absence of inactivating TP53 alteration by Next Generation Sequencing assay or
     PCR-based assay in a laboratory certified to return results for clinical purposes.

  -  Patients must have fully recovered from the acute toxic effects of all prior
     anti-cancer therapy except organ function as noted below. Patients must meet the
     following minimum washout periods prior to enrollment:

  -  Myelosuppressive chemotherapy: At least 14 days after the last dose of
     myelosuppressive chemotherapy (42 days for nitrosourea or mitomycin C).

Patients on Cohort C may have received any of the following medications without a
"wash-out" period as long as other organ function requirements are met (methotrexate must
not be given within 48 hours of ALRN-6924 planned start):

Standard maintenance therapy [any combination of vincristine, 6-mercaptopurine,
corticosteroids, and/or low-dose methotrexate (45 mg/m2/week or less)]; Hydroxyurea;
Patients on any cohort may have received intrathecal chemotherapy with methotrexate,
hydrocortisone and/or cytarabine (non-liposomal) without a "wash-out" period as long as
other organ function requirements are met (methotrexate must not be given within 48 hours
of ALRN-6924 planned start).

  -  Radiotherapy:

       -  At least 14 days after local XRT (small port, including cranial radiation);

       -  At least 90 days must have elapsed after prior TBI, craniospinal XRT or if >50%
  radiation of pelvis;

       -  At least 42 days must have elapsed if other substantial BM radiation;

       -  At least 42 days must have passed since last MIBG or other radionuclide therapy.

  -  Small molecule biologic therapy: At least 7 days following the last dose of a biologic
     agent. For agents with known adverse events occurring beyond 7 days, this duration
     must be extended beyond the time in which adverse events are known to occur. If
     extended duration is required, this should be discussed with and approved by the
     overall PI.

  -  Monoclonal antibody: At least 21 days must have elapsed after the last dose of
     antibody.

  -  Myeloid growth factors: At least 14 days following the last dose of long-acting growth
     factor (e.g. Neulasta) or 7 days following short-acting growth factor.

  -  Autologous hematopoietic stem cell transplant and stem cell boost: Patients must be at
     least 60 days from day 0 of an autologous stem cell transplant or stem cell boost.

  -  Allogeneic hematopoietic stem cell transplant or cellular therapies (including CAR-T
     cells): The patient must have no evidence of graft versus host diseaseand at least 90
     days must have elapsed after allogeneic stem cell infusion. At least 42 days must have
     elapsed after last dose of other cellular therapy.

  -  Solid Organ Transplantation: Patients with hepatoblastoma treated with liver
     transplantation will be eligible to enroll if they meet all of the following
     requirements:

       -  At least 90 days must have elapsed from the date of liver transplant;

       -  No clinical or radiographic evidence of rejection since the date of transplant;
  AND

       -  All organ function requirements are met.

  -  Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Biopsy, CNS
     shunt placement/revision, and central line placement/removal are not considered major.

  -  MDM2 inhibitors: Patients for Cohorts A and C may have received prior MDM2 inhibitor
     therapy. Patients in Cohort B must not have received prior MDM2 inhibitor therapy.
     Patients in all cohorts must not have received dual MDM2/MDMX inhibition.

  -  Participants must have normal organ function as defined below.

  -  Bone Marrow Function for Subjects in Cohorts A and B without Bone Marrow Involvement
     by Disease:

       -  Absolute neutrophil count ≥1,000 /uL

       -  Platelets ≥75,000 /uL and transfusion independent, defined as not receiving a
  platelet transfusion for at least 5 days prior to CBC documenting eligibility.

  -  Hematologic Requirements for Subjects in Cohorts A and B with Bone Marrow Involvement
     by Disease:

       -  Absolute neutrophil count ≥750 /uL

       -  Platelets ≥50,000 /uL (may receive platelet transfusions)

       -  Not known to be refractory to red cell and/or platelet transfusions.

  -  Bone Marrow Function for Subjects in Cohorts C with Acute Leukemia

     ---Not known to be refractory to red cell and/or platelet transfusions

  -  Hepatic Function:

       -  Total bilirubin ≤ 1.5 x upper limit of normal for age except for patients with
  known Gilbert syndrome who may enroll using direct bilirubin ≤ 1.5 x upper limit
  of normal for age as bilirubin criterion

       -  ALT (SGPT) ≤ 3 x upper limit of normal (135 U/L). For the purpose of this study,
  the ULN for ALT is 45 U/L. Patients with acute leukemia AND leukemic infiltration
  of the liver may enroll to Cohort C if ALT < grade 2 and total bilirubin meets
  above requirement.

       -  Serum albumin > 2 g/dL

  -  Renal Function:

       -  A serum creatinine within protocol limits based on age/sex. OR

       -  Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels
  greater than the above age/sex maximum allowed values.

  -  Adequate Cardiac Function: QTc < 480 msec

  -  For patients with CNS tumors (primary or metastatic), any baseline neurologic deficits
     (including seizure) must be stable for at least one week prior to study enrollment.
     Patients with CNS tumors receiving corticosteroids must be on a stable or decreasing
     dose at time of study entry.

  -  Ability to understand and/or the willingness of the patient (or parent or legally
     authorized representative, if minor) to provide informed consent, using an
     institutionally approved informed consent procedure.

  -  Participants of child-bearing or child-fathering potential must agree to use adequate
     contraception (hormonal birth control; intrauterine device; double barrier method; or
     total abstinence) throughout their participation, including up until 30 days after
     last dose of ALRN-6924.

Exclusion Criteria:

  -  Patients receiving medications within 48 hours of enrollment that are primarily
     cleared by organic anion transporter polypeptide [OATP] members OATP1B1 and OATP1B3

  -  Pregnant participants will not be entered on this study given that the effects of
     ALRN-6924 on the developing human fetus are unknown.

  -  Breastfeeding mothers are not eligible, because there is an unknown risk for adverse
     events in nursing infants secondary to treatment of the mother with ALRN-6924.

  -  History of allergic reactions attributed to compounds of similar chemical or biologic
     composition to ALRN-6924.

  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
     infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
     arrhythmia, or psychiatric illness/social situations that would limit compliance with
     study requirements.

  -  Patients with a known history of HIV, hepatitis B, and/or hepatitis C (testing not
     required as part of screening).

  -  Patients with a known personal history of angioedema or known family history of
     hereditary angioedema.

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