ALRN-6924 in Treating Children with Recurrent or Refractory Solid Tumors, Brain Tumors, or Lymphoma

Status: Active

Description

This phase I trial studies the best dose and side effects of ALRN-6924 in children with solid tumors, brain tumors, or lymphoma that have come back or do not respond to treatment. ALRN-6924 is a drug that blocks certain proteins in tumor cells called MDM2 and MDMX and may stop tumor growth and may cause tumor cells to die.

Eligibility Criteria

Inclusion Criteria

  • 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
  • For Cohorts A and B: 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 wild type (WT) TP53 * Diagnosis of malignant rhabdoid tumor and WT TP53. For the purposes of this study, a diagnosis of malignant rhabdoid tumor will include histologic diagnosis (CNS atypical teratoid/rhabdoid tumor, rhabdoid tumor of the kidney or rhabdoid tumor of the soft tissue) AND molecular confirmation (loss of INI1 or BRG1 protein staining by immunohistochemistry [IHC], or documentation of SMARCB1 or SMARCA4 mutation or loss) * 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, CNS tumor, or lymphoma with PPM1D amplification, high-copy gain, or PPM1D activating mutation and WT TP53 * Solid tumor or lymphoma with TET2 loss or loss-of-function mutation and WT TP53 ** Note: Testing for MDM2, MDMX, TP53, SMARCB1, SMARCA4, PPM1D 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 acute myeloid leukemia (AML), acute lymphoblastic leukemia (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
  • For Cohort C: 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
  • For Cohort C: Subjects must have CNS1 or CNS2 disease
  • Absence of inactivating TP53 alteration by next generation sequencing assay or polymerase chain reaction (PCR)-based assay in a laboratory certified to return results for clinical purposes. If assessment of TP53 on material obtained from the current relapse will cause an unacceptable delay or if the current relapse will not be biopsied, the patient may enroll and initiate treatment based upon results obtained at the time of prior biopsy. Such patients may continue on protocol therapy in consultation with the overall principal investigator if subsequent testing reveals a TP53 alteration. For the purposes of this study, a patient will be considered to have wildtype TP53 if they have had clinical laboratory testing that does not return any of the following findings: * Clinical diagnosis of Li-Fraumeni cancer predisposition syndrome * Pathogenic or likely pathogenic germline variant in TP53. Variants of uncertain significance (according to American College of Medical Genetics [ACMG] guidelines) are excluded from this definition and will be considered TP53 wild type * Known deleterious or suspected deleterious somatic variant in TP53 present at an allele frequency > 5% (for reports that provide allele frequency) or at any frequency (for reports that do not provide allele frequency). Variants of uncertain significance (e.g., Tier 4 variants on OncoPanel or Tier 3 variants by Association for Molecular Pathology [AMP]/College of American Pathologists [CAP]/American Society of Clinical Oncology [ASCO] guidelines) are excluded from this definition and will be considered TP53 wild type * Deletion of TP53 on chromosome 17, either focal, chromosome level or arm level, as identified by cytogenetic testing or through next generation sequencing-based estimation of gene copy number of TP53 * Patients with retinoblastoma are not required to have TP53 sequencing if tissue is not available for sequencing. For patients with retinoblastoma who do have available tissue, they must have confirmation of WT TP53 on the most recently sequenced sample
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function. 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/m^2/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 radiation therapy (XRT) (small port, including cranial radiation); ** At least 90 days must have elapsed after prior total body irradiation (TBI), craniospinal XRT or if > 50% radiation of pelvis; ** At least 42 days must have elapsed if other substantial bone marrow (BM) radiation; ** At least 42 days must have passed since last meta-iodobenzylguanidine (MIBG) scan 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 principal investigator (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 chimeric antigen receptor [CAR]-T cells): The patient must have no evidence of graft versus host disease and 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 as long as they satisfy small molecule biologic therapy section. Patients in Cohort B must not have received prior MDM2 inhibitor therapy. Patients in all cohorts must not have received dual MDM2/MDMX inhibition
  • Absolute neutrophil count >= 1,000/uL (for subjects in cohorts A and B without bone marrow involvement by disease)
  • Platelets >= 75,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to complete blood count (CBC) documenting eligibility (for subjects in cohorts A and B without bone marrow involvement by disease)
  • Absolute neutrophil count >= 750/uL (for subjects in cohorts A and B with bone marrow involvement by disease)
  • Platelets >= 50,000/uL (may receive platelet transfusions) (for subjects in cohorts A and B with bone marrow involvement by disease)
  • Not known to be refractory to red cell and/or platelet transfusions (for subjects in cohorts A and B with bone marrow involvement by disease)
  • Not known to be refractory to red cell and/or platelet transfusions (for subjects in cohorts C with acute leukemia)
  • 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
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (135 U/L) * For the purpose of this study, the upper limit of normal (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
  • Serum creatinine based on age/sex as follows: * Age: Maximum serum creatinine (mg/dL): ** 1 to < 2 years; Male: 0.6; Female: 0.6 ** 2 to < 6 years; Male: 0.8; Female: 0.8 ** 6 to < 10 years; Male:1; Female: 1 ** 10 to < 13 years; Male: 1.2; Female: 1.2 ** 13 to < 16 years; Male: 1.5; Female: 1.4 ** >= 16 years; Male: 1.7; Female: 1.4 OR Creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels greater than the above age/sex maximum allowed values
  • Corrected QT interval (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 human immunodeficiency virus (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

Locations & Contacts

Massachusetts

Boston
Boston Children's Hospital
Status: Active
Contact: Steven G. DuBois
Phone: 617-632-5460
Email: SDUBOIS2@PARTNERS.ORG
Dana-Farber Cancer Institute
Status: Active
Contact: Steven G. DuBois
Phone: 617-632-5460
Email: SDUBOIS2@PARTNERS.ORG

Texas

Houston
Texas Children's Hospital
Status: Active
Contact: Jodi Muscal
Phone: 832-824-4632
Email: jamuscal@txch.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended pediatric phase 2 dose of MDM2/MDMX inhibitor ALRN-6924 (ALRN-6924) as monotherapy in children with relapsed or refractory TP53 wild type solid tumors, central nervous system (CNS) tumors or lymphoma, and in combination with low-dose cytarabine in children with relapsed or refractory TP53 wild type acute leukemia.

II. To describe the toxicities of ALRN-6924 given as monotherapy or in combination with low-dose cytarabine in children with advanced cancer.

SECONDARY OBJECTIVES:

I. To describe the pharmacokinetics of ALRN-6924 in children with advanced cancer.

II. To describe the objective response rate of ALRN-6924 monotherapy in children with relapsed or refractory solid tumors, CNS tumors or lymphoma, and of ALRN-6924 in combination with low-dose cytarabine in children with relapsed or refractory acute leukemia.

EXPLORATORY OBJECTIVES:

I. To describe the pharmacodynamic effects of ALRN-6924 in children with advanced cancer.

II. To investigate tumor, peripheral blood, and leukemic blast biomarkers associated with response to ALRN-6924 in children with advanced cancer.

III. To bank tumor material, germline deoxyribonucleic acid (DNA), peripheral blood, and bone marrow for potential future research for participating subjects who provide additional consent.

OUTLINE: This is a dose-escalation study of MDM2/MDMX inhibitor ALRN-6924. Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive MDM2/MDMX inhibitor ALRN-6924 intravenously (IV) over 1 hour on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive cytarabine IV and MDM2/MDMX inhibitor ALRN-6924 IV over 1 hour on days 1, 8, and 15. Patients with certain diseases may also receive cytarabine intrathecally (IT) on days 1 and 15 of cycles 1 and 2 and on day 15 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Steven G. DuBois

Trial IDs

Primary ID 18-284
Secondary IDs NCI-2018-02766
Clinicaltrials.gov ID NCT03654716