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Dexrazoxane Hydrochloride

Gemtuzumab Ozogamicin

Maro Ohanian

This phase II trial studies how well dexrazoxane hydrochloride works in preventing heart-related side effects of chemotherapy in participants with blood cancers, such as acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and myeloproliferative neoplasms. Chemoprotective drugs, such as dexrazoxane hydrochloride, may protect the heart from the side effects of drugs used in chemotherapy, such as cladribine, idarubicin, cytarabine, and gemtuzumab ozogamicin, in participants with blood cancers.

PRIMARY OBJECTIVES:

I. To estimate the percentage of patients experiencing a decrease in left ventricular ejection fraction (LVEF) of 10 percent from baseline or decrease in LVEF below the normal limit of 50% during treatment with dexrazoxane (dexrazoxane hydrochloride) combined with cladribine, idarubicin, cytarabine, and Mylotarg (gemtuzumab ozogamicin) within the first 6-months of treatment.

SECONDARY OBJECTIVES:

I. To estimate the incidence of these cardiac symptoms while on dexrazoxane combined with idarubicin-based treatment: clinical heart failure, exertional dyspnea, orthopnea, S3 gallop, acute coronary syndrome, acute pulmonary edema and life-threatening arrhythmias.

II. To assess and monitor the change of troponin I (while still standard of care at MD Anderson) and high-sensitivity troponin T during treatment.

III. Collect safety/toxicity profile. IV. To assess rates of complete remission (CR)/complete remission with incomplete blood count recovery (CRi). (Cohorts 1-3) V. Other efficacy endpoints of interest include overall response, overall survival, event-free survival and remission duration. (Cohorts 1-3) VI. To assess the recurrence-free survival rate at 6 months. (Cohort 4)

EXPLORATORY OBJECTIVES:

I. To assess the metal chelation effects of dexrazoxane combined with chemotherapy (Mylotarg, cladribine, idarubicin, and cytarabine) by quantifying concentrations of toxic and essential metals and isotopic abundance ratios of blood and bone marrow before and during treatment.

II. To study and describe the relationship between pretreatment patient / disease characteristics (including cytogenetic and molecular abnormalities) and clinical outcomes.

III. To identify molecular biomarkers predictive of response to therapy. IV. To study and describe the relationship between patient / disease characteristics, use of intrathecal prophylaxis, and incidence of leptomeningeal disease.

V. To observe rates of fungal and other infections on the regimen. VI. To study environmental exposure data based on an environmental health assessment survey.

VII. To explore the impact of minimal residual disease (MRD) on relapse.

OUTLINE:

INDUCTION PHASE: Participants receive gemtuzumab ozogamicin intravenously (IV) over 2 hours on days 1, 4, and 7, cladribine IV over 1-2 hours on days 1-5, dexrazoxane hydrochloride IV over 15 minutes on days 1-3, idarubicin IV over 30 minutes on days 1-3, and cytarabine IV over 2 hours on days 1-5. Treatment repeats every 3-7 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION PHASE: After induction phase, participants receive gemtuzumab ozogamicin IV over 2 hours on day 1, cladribine IV over 1-2 hours on days 1-3, dexrazoxane hydrochloride IV over 15 minutes on days 1-2, idarubicin IV over 30 minutes on days 1-2, and cytarabine IV over 2 hours on days 1-3. Treatment repeats every 3-7 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Participants who go into remission or who are already in remission receive gemtuzumab ozogamicin IV over 2 hours on day 1 of course 1 and then every 2-3 months as needed. Participants also receive dexrazoxane hydrochloride IV over 15 minutes and idarubicin IV over 30 minutes on day 1, and cytarabine subcutaneously (SC) on days 1-7. Courses repeat every 3-7 weeks for 32 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 6-12 months.

Dexrazoxane Hydrochloride in Preventing Heart-Related Side Effects of Chemotherapy in Participants With Blood Cancers

Cardioprotection With Dexrazoxane in Acute Myeloid Leukemia (AML), High-Risk Myelodysplastic Syndrome (MDS), Myeloid Blast Phase of Chronic Myeloid Leukemia (CML), Ph+ AML, and Myeloid Blast Phase of Myeloproliferative Neoplasms

Metal chelation effects assessed by utilizing technologies commonly used in the geochemistry.

Will explore the impact of MRD on relapse.

Will assess a decrease in LVEF of 10 percent from baseline or decrease in LVEF below the normal limit of 50% during treatment with dexrazoxane hydrochloride combined with cladribine, idarubicin, cytarabine, and gemtuzumab ozogamicin.

Cardiac symptoms to be evaluated include: clinical heart failure, exertional dyspnea, orthopnea, S3 gallop, acute coronary syndrome, acute pulmonary edema and life-threatening arrhythmias

Troponin levels will be collected before and after the day 1 dose of idarubicin each month during induction, consolidation, and maintenance therapy.

The recurrence-free survival rate at 6 months will be a binary endpoint where the recurrence including death occurred within 6 months of treatment will be considered as "recurrence event".

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Recurrence

Fludarabine

Fludarabine phosphate

Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2g/ m2/day (days -6 to day -2)

Six doses of third-party-donor mbIL-21 expanded (KDS-1001) cells given thrice weekly for two weeks. Days may vary and KDS-1001 can be given from days 0 to 21

Cytarabine Hydrochloride

Membrane-bound Interleukin-21-Expanded Haploidentical Natural Killer Cells

The Ohio State University Comprehensive Cancer Center

Nicole Szuminski

Sumithira Vasu, MBBS

This phase I trial studies the side effects of donor natural killer (NK) cell therapy in treating patients with acute myeloid leukemia that has come back (recurrent) or has not responded to treatment (refractory). Natural killer cells are a type of immune cell. Immunotherapy with genetically modified NK cells from donors may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread.

PRIMARY OBJECTIVE:

I. To determine the safety of adoptive NK cell therapy using membrane-bound interleukin-21 (mbIL21)-expanded, off-the-shelf, third-party donor-derived NK cells in patients with relapsed/refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. Estimate the complete response (CR, CR with incomplete hematologic recovery \[CRi\] \& morphologic leukemia-free state \[MLFS\]).

II. Estimate the median relapse free survival. III. Estimate the median time to neutrophil and platelet count recovery. IV. Estimate the median duration of remission. V. Estimate the incidence of infectious complications. VI. Estimate percentage of patients receiving this regimen who are rendered transplant-eligible.

CORRELATIVE OBJECTIVES:

I. Determine the persistence of ex-vivo expanded, off-the-shelf, third-party NK cells.

II. Characterize in vivo expansion of third-party NK cells and if it differs based on the conditioning regimen as defined by NK chimerism assay.

III. Determine the immunophenotype and function of expanded cells. IV. Chimerism analysis in patients who have had post-transplant relapses.

OUTLINE: This is a dose-escalation study of membrane-bound interleukin-21-expanded haploidentical natural killer cells.

INDUCTION: Patients receive fludarabine intravenously (IV) and cytarabine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients who are \>= 60 years old, unable/unwilling to tolerate intensive chemotherapy, or disease insensitive to cytarabine (tp53, TET2 mutations) receive fludarabine IV on days -5 to -2 and decitabine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity.

All patients receive membrane-bound interleukin-21-expanded haploidentical natural killer cells via infusion on days 0, 2, 4, 7, 9, and 11.

After completion of study treatment, patients are followed up to day 56.

Trial Testing Safety of IL-21 NK Cells for Induction of R/R AML

A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-shelf, Third-party Natural Killer Cells (KDS-1001) for the Induction of Relapsed/Refractory Acute Myeloid Leukemia

Peripheral blood will be obtained before therapy, during the NK cell treatment period, and after NK cell treatment. The studies may include flow cytometry analyses and sorting and molecular studies. Donor NK-cell expansion will be defined as an absolute circulating donor-derived NK cell count that increases above the post-infusion level.

Chimerism may be determined by flow cytometry using haplotype-specific antibodies. Chimerism may be determined by short tandem repeat polymorphisms. When there is a sex-mismatch between the donor and the recipient, assays based on determining the frequency of sex-chromosomes may be used. Testing may be altered by principal investigator or designee.

Donors with distinct HLA A or B antigens that can be detected by flow cytometry will be chosen. This will enable tracking of infused cells.

The MTD will be defined as the highest safely tolerated dose where at most one patient in six experiences dose-limiting toxicity (DLT) during DLT observation period. DLT is defined as any steroid refractory acute graft versus host disease.

Toxicities will be assessed by type and grade using Common Terminology Criteria for Adverse Events version 5.0 and displayed in summary form by cohort and overall. Toxicities will be summarized and reported regardless of attribution and also only those attributed to NK cells.

Response rate with a 95% confidence interval (CI) will be reported for all evaluable patients, assuming a binomial distribution. Response rate will also be reported for those who received all 6 doses of NK cells.

Response rate with a 95% CI will be reported for all evaluable patients, assuming a binomial distribution. Response rate will also be reported for those who received all 6 doses of NK cells.

Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.

Kiadis Pharma

Sumithira Vasu

Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dexrazoxane Hydrochloride in Preventing Heart-Related Side Effects of Chemotherapy in Participants With Blood Cancers	NCT03589729	Acute Myeloid L... Blast Phase Chr... Blasts 10 Perce... High Risk Myelo... Myeloid Sarcoma Myeloproliferat... Philadelphia Ch...	Cladribine Cytarabine Dexrazoxane Hyd... Gemtuzumab Ozog... Idarubicin	12 Years -	M.D. Anderson Cancer Center
Dexrazoxane Hydrochloride in Preventing Heart-Related Side Effects of Chemotherapy in Participants With Blood Cancers	NCT03589729	Acute Myeloid L... Blast Phase Chr... Blasts 10 Perce... High Risk Myelo... Myeloid Sarcoma Myeloproliferat... Philadelphia Ch...	Cladribine Cytarabine Dexrazoxane Hyd... Gemtuzumab Ozog... Idarubicin	12 Years -	M.D. Anderson Cancer Center
Trial Testing Safety of IL-21 NK Cells for Induction of R/R AML	NCT04220684	Allogeneic Stem... Blasts 10 Perce... Recurrent Acute... Refractory Acut...	Cytarabine Hydr... Fludarabine Membrane-bound ...	18 Years -	Ohio State University Comprehensive Cancer Center
Dexrazoxane Hydrochloride in Preventing Heart-Related Side Effects of Chemotherapy in Participants With Blood Cancers	NCT03589729	Acute Myeloid L... Blast Phase Chr... Blasts 10 Perce... High Risk Myelo... Myeloid Sarcoma Myeloproliferat... Philadelphia Ch...	Cladribine Cytarabine Dexrazoxane Hyd... Gemtuzumab Ozog... Idarubicin	12 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for blasts 10 percent or more of bone marrow nucleated cells