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Myeloid Leukemia

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Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Cytarabine

Venetoclax

Fludarabine

Fludarabine phosphate

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Dose Escalation Phase:

Venetoclax plus selinexor will initially be given at dose level 1 in combination with intravenous (IV) cytarabine and fludarabine. Dosing of venetoclax and selinexor will be based on tolerability.

Intrathecal (IT) chemotherapy (IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are all acceptable) will be given.

G-CSF SC may be given.

Part 1 has been completed and RP2D has been determined to be Dose Level 2. All participants will be treated at Dose Level 2.

Dose Expansion Phase:

Two expansion cohorts will be treated at the recommended phase 2 dose (RP2D). Cohort A will include venetoclax-naïve patients, whereas Cohort B will include patients with prior exposure to venetoclax.

Selinexor

Given in to the vein (IV) or intrathecal (IT)

Given in to the vein (IV) - Because of the ongoing nationwide shortage of fludarabine, this agent may be omitted during the dose expansion phase of the trial.

Filgrastim

methotrexate/hydrocortisone/cytarabine

Jeffrey E. Rubnitz, MD, PhD

Dennis Kuo, MD

Kelly Faulk, MD

Andrew Place, MD, PhD

Maria-Luisa Sulis, MD

Sarah K. Tasian, MD

Sarah Tasian, MD

Brianna Smith, MD

Kathleen Ludwig, MD

Kenneth Heym, MD

Eric Schafer, MD

The purpose of this study is to test the safety and determine the best dose of venetoclax and selinexor when given with chemotherapy drugs in treating pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has come back (relapsed) or did not respond to treatment (refractory).

Primary Objective

* To determine the safety and tolerability of selinexor and venetoclax in combination with chemotherapy in pediatric patients with relapsed or refractory AML or ALAL.

Secondary Objectives

* Describe the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the recommended phase 2 dose (RP2D).
* Describe the overall survival of patients treated at the RP2D.

Exploratory Objectives

* Explore associations between leukemia cell genomics, BCL2 family member protein quantification, BH3 profiling, and response to therapy as assessed by minimal residual disease (MRD) and variant clearance using cell-free deoxyribonucleic acid (DNA) (cfDNA).
* Describe the quality of life of pediatric patients undergoing treatment with selinexor and venetoclax in combination with chemotherapy and explore associations of clinical factors with patient-reported quality of life outcomes.
* Describe the clinical and genetic features associated with exceptional response to the combination of venetoclax and selinexor without the addition of chemotherapy.

This study will include two phases. The dose-escalation phase will characterize the dose-limiting toxicity (DLT) and determine the recommended phase 2 dose (RP2D) of venetoclax plus selinexor with and without chemotherapy. Two expansion cohorts (cohort A, patients without prior exposure to venetoclax; cohort B, patients with prior exposure to venetoclax) will further assess the safety and will explore the efficacy at the RP2D.

Dosing of venetoclax and selinexor will be based on tolerability. Venetoclax will be given orally (po) once daily on days 1 through 21 and selinexor will be given orally (po) starting on days 1, 8, and 15 OR 1, 3, 8, 10, 15, and 17. Beginning on day 16, patients also receive fludarabine phosphate intravenously (IV) daily on days 16-20, cytarabine IV daily on days 16-20, and granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) daily on days 16-20. G-CSF may be omitted or extended at the discretion of the treating physician. Intrathecal (IT) chemotherapy will be given prior to cycle 1, but may be delayed if clinically indicated. IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are all acceptable. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly IT therapy beginning on day 8, until the cerebrospinal fluid becomes free of leukemia.

Chemotherapy is scheduled to begin on Day 16; however, patients with exceptional responses may, at the discretion of the treating physician, receive chemotherapy (fludarabine and cytarabine) on days 16-20 and continue venetoclax through day 21 and selinexor through day 15 or 17 according to dose level. Alternatively, exceptional responders may continue venetoclax through day 28 and selinexor once or twice weekly according to dose level without chemotherapy and then undergo re-evaluation at day 29. For patients who do not receive chemotherapy on day 16-20, chemotherapy may be omitted completely or may be given on days 30-34 at the discretion of the treating physician.

Patients may receive up to 4 cycles of therapy in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.

Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

A Phase I and Expansion Cohort Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

The primary endpoint is the recommended phase 2 dose (RP2D) of venetoclax plus selinexor plus chemotherapy.

A count of the number of patients treated at each dose level during the dose escalation phase will be provided

A count of the number of patients at each dose level who experience a Non-Hematologic DLT defined as any grade 3 or higher event that occurs within 35 days of the first dose and is at least possibly attributable to study drug administration (venetoclax, selinexor, fludarabine and/or cytarabine).

A count of the number of patients at each dose level who experience a Hematologic DLT defined as failure to recover counts (ANC \> 500/µl and platelet count \> 25,000/µl) by day 43 from the start of chemotherapy unless the delay in count recovery is due to another identifiable factor.

CR is defined as bone marrow with \< 5% blasts confirmed by flow cytometry, ANC ≥ 500/μL and platelets ≥ 50,000/μL without transfusions, and no evidence of extramedullary disease.

CRi is defined as bone marrow with \< 5% blasts confirmed by flow cytometry, ANC \< 500/μL or platelets \< 50,000/μL without transfusions, and no evidence of extramedullary disease

Overall survival is defined as the time elapsed from protocol enrollment to death, with data for living patients censored at last follow-up. We will report KM estimates with 95% CIs.

Exceptional Response is defined as patients who have at least 2-log (100-fold) reduction in bone marrow MRD at day 15 compared to bone marrow blast percentage at enrollment.

Karyopharm Therapeutics Inc

AbbVie

Gateway for Cancer Research

St. Jude Children's Research Hospital

Immune System Diseases

Neoplasm Metastasis

Syndrome

Lymphoma

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Neoplasms

Preleukemia

Myelodysplastic Syndromes

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bone Marrow Diseases

Precancerous Conditions

Lymphosarcoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Antiemetics

Gastrointestinal Agents

Bone Density Conservation Agents

Cardiotonic Agents

Dexamethasone

Doxorubicin

Liposomal doxorubicin

Azacitidine

Leucovorin

Levoleucovorin

Vincristine

Calcium

Dexamethasone acetate

BB 1101

Pegaspargase

Cortisone

Calcium, Dietary

Asparaginase

Dexrazoxane

Razoxane

Hydrocortisone-17-butyrate

Dexamethasone 21-phosphate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

HIV Protease Inhibitors

Protease Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antidotes

Protective Agents

Trace Elements

Tubulin Modulators

Antimitotic Agents

For Part 1, participants will receive:

* Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort Treatment cycle is approximately 28 days for up to 4 cycles

  * Venetoclax-once daily on predetermined days per protocol
* Azacitidine-once daily on predetermined days per protocol

  * Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) with an underlying genetic condition that increases their risk for developing treatment-related toxicities. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort.

* Venetoclax-once daily on predetermined days per protocol
* Azacitidine-once daily on predetermined days per protocol
* Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

Patients with relapsed/refractory acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL) or acute leuekmai of ambiguous lineage. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort.

Cohort C: Treatment cycle is approximately 32 days for one cycle and will be a single treatment cycle:

Dosage, duration and timings as outlined in protocol.

* Venetoclax
* Dexamethasone
* Vincristine
* Doxorubicin
* Dexrazoxane
* Calaspargase pegol

  ---Short acting Erwinia preparations (recombinant or native Erwinia asparaginase) may be used for participants with known pegaspargase or calaspargase pegol allergy
* Cytarabine
* Methotrexate
* Hydrocortisone
* Leucovorin- \*Cytarabine, Methotrexate, Hydrocortisone and Leucovorin may be given more frequently if leukemia/lymphoma cells are detected in spinal fluid),

Calaspargase Pegol

Erwinia asparaginase

Andrew E Place, MD, PhD

Jessica A Pollard, MD, PhD

Elliot Stieglitz, MD

This trial is evaluating the safety and tolerability of venetoclax with chemotherapy in pediatric and young adult patients with hematologic malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia derived from myelodysplastic syndrome (MDS/AML), and acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL).

The names of the study drugs involved in this study are below. Please note this is a list for the study as a whole, participants will receive drugs according to disease cohort.

* Venetoclax
* Azacitidine
* Cytarabine
* Methotrexate
* Hydrocortisone
* Leucovorin
* Dexamethasone
* Vincristine
* Doxorubicin
* Dexrazoxane
* Calaspargase pegol
* Hydrocortisone

This is an investigator-initiated open-label multi-institutional phase I study of venetoclax combination therapy in both myeloid and lymphoid hematologic malignancies. This study is designed as a basket trial with three separate cohorts. All cohorts include a dose finding portion (Part I) followed by a dose expansion at the Recommended Phase II dose (RP2D, Part II).

This research study is looking to learn more about how Venetoclax works and aims to determine the safest, highest possible dose that can be combined with standard of care chemotherapies. Because of this, not everyone who participates in this research study may receive the same dose of the study drug. The dose participants receive will depend on the number of participants who have been enrolled in the study previously and how well the doses have been tolerated.

Study procedures include screening for eligibility as well as study treatment visits including evaluations and follow up visits.

* Cohort A: Patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia arising from MDS (MDS/AML) or treatment-related myeloid neoplasms (tMDS/AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort.
* Cohort B: Patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia arising from MDS (MDS/AML) or treatment-related myeloid neoplasms (tMDS/AML) with an underlying genetic condition that increases their risk of experiencing toxic side effects of chemotherapy. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort.
* Cohort C: Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort.

This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration (FDA) has not approved Venetoclax for use in children. However, Venetoclax is FDA-approved as a treatment for certain types of leukemia in adults. It is actively being studied in children and adults with other types of cancer. Information from these research studies has suggested that venetoclax may also be effective in treating participants with MDS or leukemia, including MDS or leukemia that did not respond to standard treatment or that has come back after standard treatment. The survival of cancer cells is controlled by proteins within the cancer cell. One of these proteins is called BCL-2. The study drug, venetoclax, blocks this protein and is thought to reduce cell survival in some cancer cells.

Venetoclax Basket Trial for High Risk Hematologic Malignancies

A Phase I Study of Venetoclax in Combination With Cytotoxic Chemotherapy, Including Calaspargase Pegol, for Children, Adolescents and Young Adults With High-Risk Hematologic Malignancies

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Andrew E. Place (Sponsor-Investigator). The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Estimate the proportion of patients who are able to receive all doses of venetoclax in cycle 1 for each cohort.

Define the percentage of patients in cohorts A\&B who successfully proceed to HSCT after treatment with venetoclax combination therapy

To determine the maximum tolerated dose (MTD of venetoclax given in combination with regimen-prescribed chemotherapy. The MTD is defined as the dose level associated with observed DLTs in \<33% of enrolled subjects

To determine the Recommended Phase 2 Dose (RP2D) of venetoclax given in combination with regimen-prescribed chemotherapy.

The RP2D is defined either as the MTD or maximum dose tested should MTD not be reached.

All grade 2 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAE v5 criteria. Incidence is the number of patients experiencing at least one treatment-related grade 2 or higher AE of any type during the time of observation.

Describe the incidence and severity of calaspargase pegol-related toxicities in subjects with relapsed/refractory ALL/LBL per collected Adverse Events using CTCAE v5 criteria.

ORR will be defined as the number of patient experiencing complete remission (CR), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete count recovery (CRi) and partial response.

CR Rate is defined as the percentage of participants that reach Complete Remission (CR):

Cohorts A and B:

* Bone marrow \< 5% myeloblasts by flow cytometry.
* No evidence of circulating blasts or extramedullary disease AND
* Platelet count ≥50k/uL (or to pre-treatment baseline) and transfusion independent for 7 days AND
* Neutrophil count ≥500 cells/uL without G-CSF support.

Cohort C (Leukemia):

* Absolute phagocyte count (APC) ≥1000/μL and platelets ≥75,000/μL without transfusions and/or exogenous growth factor support AND
* Bone marrow with evidence of trilineage hematopoiesis and with \<5% blasts AND
* No evidence of extramedullary disease

Cohort C only:

* APC \<1000/μL and/or platelets \<75,000/μL AND
* Bone marrow with \<5% blasts AND
* No evidence of extramedullary disease

CRp Rate is defined as the percentage of participant that reach to CRp:

Cohorts A \&B:

* A bone marrow with \<5% blasts AND
* No evidence of circulating blasts or extramedullary disease AND
* Recovery of absolute neutrophil counts (ANC \> 500/μL), but with insufficient recovery of platelets (PLT counts \<50,000 ul), and platelet transfusion independence (defined as no platelet transfusion x 1 week)

Cohort C:

* Absolute neutrophil count (APC ≥1000/μL) AND
* Platelets \< 75,000/μL AND
* Bone marrow with evidence of trilineage hematopoiesis and with \<5% blasts AND
* No evidence of extramedullary disease

Based on the Kaplan-Meier method defined as the time from study entry to death or censored at date last known alive

EFS is defined as the time from first dose of study treatment until evidence of progression to leukemia, relapse of MDS or leukemia after HSCT, or death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia	NCT04898894	Acute Leukemia ... Acute Myeloid L... Refractory Acut... Refractory Acut...	Venetoclax Selinexor Cytarabine Fludarabine Filgrastim Methotrexate methotrexate/hy...	2 Years - 30 Years	St. Jude Children's Research Hospital
Venetoclax Basket Trial for High Risk Hematologic Malignancies	NCT05292664	Myelodysplastic... Myelodysplastic... Myelodysplastic... Treatment-Relat... Therapy-Related... Acute Lymphobla... Acute Lymphobla... Lymphoblastic L... Lymphoblastic L... Acute Leukemia ... Acute Leukemia ...	Venetoclax Azacitidine Cytarabine Methotrexate Hydrocortisone Leucovorin Dexamethasone Vincristine Doxorubicin Dexrazoxane Calaspargase Pe... Erwinia asparag...	1 Year - 40 Years	Dana-Farber Cancer Institute
Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia	NCT04898894	Acute Leukemia ... Acute Myeloid L... Refractory Acut... Refractory Acut...	Venetoclax Selinexor Cytarabine Fludarabine Filgrastim Methotrexate methotrexate/hy...	2 Years - 30 Years	St. Jude Children's Research Hospital
Venetoclax Basket Trial for High Risk Hematologic Malignancies	NCT05292664	Myelodysplastic... Myelodysplastic... Myelodysplastic... Treatment-Relat... Therapy-Related... Acute Lymphobla... Acute Lymphobla... Lymphoblastic L... Lymphoblastic L... Acute Leukemia ... Acute Leukemia ...	Venetoclax Azacitidine Cytarabine Methotrexate Hydrocortisone Leucovorin Dexamethasone Vincristine Doxorubicin Dexrazoxane Calaspargase Pe... Erwinia asparag...	1 Year - 40 Years	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for acute leukemia of ambiguous lineage in relapse