A Study of Revumenib in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia

Study Overview
=================
Brief Summary
-----------------
This phase II trial tests the safety and best dose of revumenib when given together with chemotherapy, and how well the treatment regimen works for infants and young children with leukemia that has come back (relapsed) or does not respond to treatment (refractory) and is associated with a KMT2A (MLL) gene rearrangement (KMT2A-R). Revumenib is an oral medicine that directly targets the changes that occur in a cell with a KMT2A rearrangement and has been shown to specifically kill these leukemia cells in test tubes and animals. Drugs used in chemotherapy, such as vincristine, prednisone, asparaginase, fludarabine and cytarabine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial is being done to find out if the combination of revumenib and chemotherapy may help to treat the cancer cells better than either treatment alone.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of revumenib (SNDX-5613) administered in combination with chemotherapy in patients with relapsed or refractory (R/R) KMT2A-rearranged (KMT2A-R) acute lymphoblastic leukemia (ALL). II. To estimate the minimal residual disease (MRD) negative remission rate of patients with R/R infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics (PK) of SNDX-5613 administered with chemotherapy in patients with R/R infant KMT2A-R ALL. II. To estimate the 18-month event-free survival (EFS) of patients with R/R infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy. III. To estimate 18-month overall survival (OS) of patients with R/R infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy. IV. To characterize the tolerability of SNDX-5613 given as monotherapy in patients with R/R infant KMT2A-R ALL. EXPLORATORY OBJECTIVE: I. To assess the biologic activity of SNDX-5613 administered with chemotherapy in patients with R/R KMT2A-R ALL. OUTLINE: Patients with ALL, ALAL or MPAL are assigned to 1 of 2 regimens. Patients with AML are assigned to Regimen B. REGIMEN A: COMBINATION CYCLE 1: Patients receive revumenib orally (PO) or via nasogastric (NG), nasojejunal (NJ), nasoduodenal (ND) or gastrostomy tube (G-tube). Patients also receive 3-drug re-induction consisting of vincristine intravenously (IV), prednisone or prednisolone PO or via NG, ND, NJ, or G-tube, pegaspargase or calaspargase pegol-mknl IV, as well as methotrexate (MTX) intrathecally (IT), hydrocortisone IT, and cytarabine IT. Patients who have early progressive disease may continue to Combination Cycle 2 early before fully completing cycle 1. COMBINATION CYCLE 2: Patients receive revumenib PO, FLA consisting of fludarabine IV and high-dose cytarabine IV. After completion of Combination Cycle 2, patients who experienced early progressive disease in Combination Cycle 1 continue to Combination Cycle 3. All other patients proceed to Monotherapy. COMBINATION CYCLE 3: Patients receive revumenib PO, FLA as in Combination Cycle 2, MTX IT, hydrocortisone IT, and cytarabine IT. MONOTHERAPY: Patients receive revumenib PO for up to 12 cycles on study. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated. REGIMEN B: COMBINATION CYCLES 1-2: Patients receive revumenib PO, NG, ND, NJ, or G-tube, FLA, MTX IT, hydrocortisone IT, and cytarabine IT for 2 cycles on study. MONOTHERAPY: Patients receive revumenib PO for up to 12 cycles on study. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated. All patients also undergo echocardiogram (ECHO) or multi-gated acquisition (MUGA) scans and collection of blood on study, and bone marrow collection throughout the trial.

Official Title
-----------------
A Phase 2 Study of SNDX-5613 in Combination With Chemotherapy for Patients With Relapsed or Refractory KMT2A-Rearranged Infant Leukemia

Conditions
-----------------
Recurrent Acute Leukemia of Ambiguous Lineage, Recurrent Acute Lymphoblastic Leukemia, Recurrent Mixed Phenotype Acute Leukemia, Refractory Acute Leukemia of Ambiguous Lineage, Refractory Acute Lymphoblastic Leukemia, Refractory Mixed Phenotype Acute Leukemia

Intervention / Treatment
-----------------
* Procedure: Biospecimen Collection
* Drug: Calaspargase Pegol
* Drug: Cytarabine
* Procedure: Echocardiography
* Drug: Fludarabine Phosphate
* Drug: Hydrocortisone Sodium Succinate
* Drug: Methotrexate
* Procedure: Multigated Acquisition Scan
* Drug: Pegaspargase
* Drug: Prednisolone
* Drug: Prednisone
* Drug: Revumenib
* Drug: Vincristine Sulfate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must be 1 month to < 6 years old at the time of study enrollment and must have had initial diagnosis of leukemia at < 2 years old. Patients must have KMT2A-rearranged acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage (ALAL), or mixed phenotype acute leukemia (MPAL), which is determined to be refractory or in first marrow relapse. Patients who have experienced lineage switch to acute myeloid leukemia (AML) are eligible assuming documented prior diagnosis of KMT2A-rearranged ALL/ALAL/MPAL. All patients must undergo cytogenetics and fluorescence in situ hybridization (FISH) testing of a relapsed/refractory blast sample at a Children's Oncology Group (COG)-approved laboratory for KMT2A-R status determination and the presence of a KMT2A- rearrangement must be confirmed by central review. Cytogenetics results must be submitted for central review by Day 10 of Cycle 1, for confirmation of KMT2A-R status. Patients enrolled with refractory disease may utilize initial diagnostic cytogenetics for eligibility and submission for central review. Patients will be eligible to remain on protocol therapy if KMT2A-R is confirmed by central review. Additional methods of assessing for KMT2A-R may be considered if FISH does not detect the rearrangement. Disease status at time of enrollment must be one of the following: 1st relapse: Any recurrence of marrow disease, with or without other extramedullary sites(s), at any point after achieving remission. (Remission-1, per definition below) meeting one of these criteria: Relapse M1: M1 morphology (< 5% blasts) + at least 2 confirmatory tests showing >= 1% blasts (testing includes flow, cytogenetics, polymerase chain reaction (PCR)/next-generation sequencing (NGS) of immunoglobulin (Ig)/T-cell receptor (TCR) rearrangement, and/or PCR or NGS of fusion gene identical to diagnosis), OR Relapse M2: M2 morphology (5-25% blasts) + 1 confirmatory test showing > 1% blasts, OR Relapse M3: M3 morphology (> 25% blasts) Refractory, or failure to achieve Remission-1: Remission-1 is defined as < 1% marrow blasts by flow minimal residual disease (MRD) and resolution of extramedullary disease by the end of Consolidation, or 2 courses of frontline chemotherapy. Central Nervous System (CNS) disease: Patients must have CNS1 or CNS2 status and no clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial palsy. Patients with CNS3 disease may receive antecedent intrathecal chemotherapy to achieve CNS1 or CNS2 status prior to enrollment. Patients with a history of CNS chloromatous disease are required to have no radiographic evidence of CNS disease prior to enrollment. White blood cell (WBC) must be < 50,000/uL at the time of study enrollment. Patients can receive cytoreduction with hydroxyurea and/or corticosteroids for up to 7 days prior to enrollment. Patients >= 12 months of age must have a performance status by Lansky Scale of >= 50%. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: >= 14 days must have elapsed after the completion of other cytotoxic therapy, including patients who relapse during pre-Maintenance upfront therapy, with these specific exceptions: cytoreduction with hydroxyurea and/or corticosteroids, and intrathecal chemotherapy, which have no required washout periods. For patients who relapse during upfront Maintenance therapy, >= 7 days must have elapsed after the last dose of chemotherapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy. NOTE: Cytoreduction with hydroxyurea and/or corticosteroids is permitted prior to enrollment for patients with WBC >= 50,000/uL, and by provider discretion regardless of WBC, to reduce potential risk of differentiation syndrome with SNDX-5613 initiation. Hydroxyurea and/or corticosteroids may be given for up to 7 days, with no wash-out required. NOTE: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy that is given up to 7 days prior to the initiation of protocol therapy counts as protocol therapy and not prior anti-cancer therapy. Intrathecal chemotherapy given > 7 days prior does not count as protocol therapy. NOTE: Prior exposure to fludarabine and cytarabine (FLA) is permitted. Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or ANC counts): >= 7 days after the last dose of agent. Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade =< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to Grade 2 or lower as outlined in the inclusion/exclusion criteria. Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or >= 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator. Interleukins, Interferons and Cytokines (other than hematopoietic growth factors): >=21 days after the completion of interleukins, interferon, or cytokines Stem cell infusions (with or without total body irradiation (TBI): Allogeneic (non-autologous) bone marrow or stem cell transplant, or stem cell boost: >= 84 days after infusion Donor leukocyte infusion: >= 28 days Cellular Therapy: >= 28 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) Radiation Therapy (XRT)/External Beam Irradiation including protons: >= 14 days after local XRT; >= 84 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow radiation. A serum creatinine based on age as follows: Age 1 month to < 6 months: maximum serum creatinine 0.4 mg/dL Age 6 months to < 1 year: maximum serum creatinine 0.5 mg/dL Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL OR a 24-hour urine Creatinine clearance >= 70 mL/min/1.73 m^2 OR a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard). NOTE: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility. A direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, unless disease related Serum glutamic-pyruvic transaminase (SGPT) alanine aminotransferase (ALT) =< 135 U/L (3 x ULN) unless disease related. Note: For the purpose of eligibility, the ULN for SGPT (ALT) has been set to the value of 45 U/L Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram. Corrected QT interval using Fridericia formula (QTcF) of < 450 msec (using the average of triplicate measurements) NOTE: There are no specific electrolyte parameters for eligibility. However, it should be noted that, to limit QTc prolongation risk, patients must maintain adequate potassium and magnesium levels to initiate and continue SNDX-5613 on protocol therapy. Exclusion Criteria: Patients with isolated extramedullary leukemia. Patients diagnosed with Down syndrome. Patients known to have one of the following syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome. Patients with a secondary KMT2A-R leukemia that developed after treatment of prior malignancy with cytotoxic chemotherapy. Patients with a history of congenital prolonged QT syndrome, congestive heart failure or uncontrolled arrhythmia in the past 6 months prior to study enrollment. Patients unable to take enteral medications. Acceptable routes of administration for SNDX-5613 include: oral (PO), nasogastric (NG) tube, nasojejunal (NJ) tube, nasoduodenal (ND) and gastrostomy tube (G-tube). Patients with an active, uncontrolled infection, further defined below: Positive bacterial blood culture within 48 hours of study enrollment Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved. For patients with Clostridium (C.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline Active viral or protozoal infection requiring IV treatment Human immunodeficiency virus (HIV)-infected patients are eligible if on effective anti-retroviral therapy that does not interact with planned study agents and with undetectable viral load within 6 months of enrollment. Patients with active acute graft-versus-host disease (GVHD) > Grade 0, or chronic GVHD > Grade 0 (unless skin only) are not eligible. Patients with acute or chronic skin GVHD that is =< Grade 1 are eligible. Patients who have received a prior solid organ transplantation. Patients with known Charcot-Marie-Tooth disease, if treating on Regimen A (with vincristine). CYP3A4 Inhibitors or Inducers: Patients who require concomitant therapy with moderate or strong CYP3A4 inhibitors or inducers, as these are prohibited during the chemotherapy combination cycles. These agents should be discontinued at least 7 days prior to starting protocol therapy. Patients who may be switched to an alternate therapy that is not a moderate or strong CYP3A4 inhibitor or inducer at least 7 days prior to enrollment are eligible. Concomitant use of strong CYP3A4 inhibitor -azole antifungals are permitted during SNDX-5613 monotherapy cycles, with appropriate SNDX-5613 dose modification. Investigational Drugs: Patients who are currently receiving another investigational drug. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents (exceptions: hydroxyurea and corticosteroids, which may be used as cytoreduction prior to enrollment). Anti-GVHD Agents: Patients who are receiving cyclosporine, tacrolimus, or other systemic agents to treat graft-versus-host disease post bone marrow transplant. Patients should discontinue anti-GVHD agents > 7 days prior to enrollment and have no evidence of worsening GVHD. Topical steroids are permitted. Patients who have previously been treated with SNDX-5613. Prior exposure to other menin inhibitors is permitted. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study. All patients and/or their parents or legal guardians must sign a written informed consent. All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (revumenib, 3-drug re-induction, FLA)<br>See Detailed Description. | Procedure: Biospecimen Collection<br>* Undergo collection of blood and bone marrow samples<br>* Other names: Specimen Collection;Drug: Calaspargase Pegol<br>* Given IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cytarabine<br>* Given IV and IT<br>* Other names: WR-28453;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Hydrocortisone Sodium Succinate<br>* Given IT<br>* Other names: Solu-Glyc;Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA scan<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisolone<br>* Given PO or via NG, NJ, ND or G-tube<br>* Other names: Sterane;Drug: Prednisone<br>* Given PO or via NG, NJ, ND or G-tube<br>* Other names: SK-Prednisone;Drug: Revumenib<br>* Given PO or via NG, NJ, ND or G-tube<br>* Other names: SNDX5613;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Regimen B (revumenib, FLA)<br>COMBINATION CYCLES 1-2: Patients receive revumenib PO, NG, ND, NJ, or G-tube, FLA, MTX IT, hydrocortisone IT, and cytarabine IT for 2 cycles on study. MONOTHERAPY: Patients receive revumenib PO for up to 12 cycles on study. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated. Patients also undergo ECHO or MUGA scans and collection of blood on study, and bone marrow collection throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood and bone marrow samples<br>* Other names: Specimen Collection;Drug: Cytarabine<br>* Given IV and IT<br>* Other names: WR-28453;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Hydrocortisone Sodium Succinate<br>* Given IT<br>* Other names: Solu-Glyc;Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA scan<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Revumenib<br>* Given PO or via NG, NJ, ND or G-tube<br>* Other names: SNDX5613;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) (Safety Phase) | For determination of recommended phase 2 dose (RP2D)-lymphoid (L) directed chemotherapy block, patient will be considered as being evaluable for dose-limiting toxicities (DLT) if: (1) the patient receives at least 66 doses of the first planned 28 days (84 doses) of SNDX- 5613 for Cycle 1 (for patients with delayed SNDX-5613 shipment, will count 28 days from the start of SNDX-5613); or (2) the patient experiences a DLT after the start of SNDX-5613 in that cycle. For determination of RP2D-myeloid (M) directed chemotherapy block, patients in Regimen B will be considered as being evaluable for DLT if: (1) the patient receives at least 66 doses of the first planned 28 days (84 doses) of SNDX-5613 for Cycle 1 (for patients with delayed SNDX-5613 shipment, count 28 days from the start of SNDX-5613); or (2) the patient experiences a DLT after the start of SNDX-5613 in that cycle. | Cycles 1 and 2 for Regimen A, and Cycle 1 for Regimen B | 
| Minimal residual disease (MRD) negative remission rate (Expansion Phase) | A patient with relapsed/refractory (R/R) infant KMT2A-R ALL will be included in the primary analysis of MRD negative remission rate if the patient is enrolled at RP2D-L and RP2D-M (in the safety phase or the expansion phase) and receives at least one dose of protocol treatment. This response rate will be estimated using the approach of Jung and Kim. The corresponding 95% confidence interval will be calculated using the approach of Koyama and Chen. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving desired pharmacokinetics (PK) during the expansion phase | Analyses will be conducted for lymphoid and myeloid blocks separately and then combined. Will monitor if there is evidence that the proportion of patients achieving desired PK is considerably lower than 90% using the Pocock stopping boundaries. | Pre-dose on day 8 of cycles 1-3; 1 hour (hr) and 4 hr post-dose on days 1 and 8 of cycle 1 and day 8 only during cycles 2-3; Pre-dose on day 1 during monotherapy cycles | 
| Estimation of 18-month event-free survival (EFS) rate | Will be estimated using the Kaplan-Meier method. | Time from date of enrollment to date of treatment failure, relapse, second or secondary malignancy (SMN), or death due to any cause, whichever occurs first, assessed up to 18 months | 
| Estimation of 18-month overall survival (OS) rate | Will be estimated using the Kaplan-Meier method. | Time from date of enrollment to death due to any cause, assessed up to 18 months | 
| Characterization of tolerability of SNDX-5613 given as monotherapy | Grade 3+ adverse events (AEs) will be summarized among patients receiving monotherapy, by cycles, and the proportion of patients having grade 3+ AEs will be estimated. | Up to 4 years |