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Mylotarg

Marcos de Lima, MD

Primary Objective:

To determine the safety and maximum tolerated dose of CMA-676 as part of an intensive but nonmyeloablative preparative regimen in older or medically infirm patients undergoing mini-allogeneic peripheral blood stem cell transplantation

Secondary Objectives:

1. To evaluate response rates, engraftment kinetics and degree of chimerism achievable with this strategy.
2. To evaluate disease-free and overall survival and relapse rates.
3. To evaluate the need and ability to give multiple cycles of Mylotarg plus FA and mobilized DLI in patients not achieving complete remission.

Mylotarg is a novel immunoconjugate directed against the CD33 antigen found on most leukemia cells. This humanized murine IgG4 monoclonal antibody is tagged with the toxin, calicheamicin. In equal molar concentrations, calicheamicin is about 3200 times more potent than adriamycin. In a Phase I study involving adult patients with relapse AML, Mylotarg has been shown to have significant anti-leukemia activity with little toxicity. The most concerning side effects of Mylotarg were prolonged neutropenia and thrombocytopenia. Phase II studies have also demonstrated good efficacy with little toxicity.

The goal of this proposal is to include Mylotarg in a nonmyeloablative preparative regimen similar to FAI used at MD Anderson Cancer Center. The hypothesis is that Mylotarg will provide potent anti-leukemic effects without adding toxicity to the mini-allogeneic bone marrow transplant regimen. A more potent anti-leukemic response may increase the complete remission rates and induce a state of minimal residual disease (MRD). Therefore, the Graft vs. Leukemia (GVL) effect of allogeneic transplantation will have a better chance for success. In addition, the administration of donor cells after Mylotarg should ameliorate the cytopenias previously associated with Mylotarg. This medication likely will be well-tolerated.

Patients with high-risk hematopoietic malignancies that express CD33 (i.e. AML, ALL, CML and MDS) will be included. We will enroll older patients (\>55 years old) or medically infirm patients who are unable to tolerate standard allogeneic bone marrow transplant. Patients will be evaluated at 28 days post-transplant for evidence of response. Those with residual disease may be eligible for additional Mylotarg given together with donor lymphocyte infusions. Additional courses of Mylotarg may improve overall survival in this poor prognosis group.

Nonmyeloablative Preparative Regimen Using Mylotarg for Patients With High Risk Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML) and Myelodysplastic Syndrome (MDS)

Allogeneic Stem Cell Transplantation Using Mylotarg (CMA-676) Plus Nonmyeloablative Chemotherapy in Older or Medically Infirm Patients With High-Risk Acute Leukemia (ALL), Chronic Myelogenous Leukemia (CML) or Myelodysplastic Syndrome (MDS)

Wyeth is now a wholly owned subsidiary of Pfizer

M.D. Anderson Cancer Center

Anti-Infective Agents

Cytarabine

Clofarabine

Antimetabolites

Clofarabine, ara-C

FLAMSA

Stefanie Buchholz, Dr.

Arnold Ganser, Prof. Dr.

Michael Pfreundschuh, Prof. Dr.

Dietger Niederwieser, Prof. Dr.

ClAraC (consisting of one dose of clofarabine and ara-C for five days) or FLAMSA (consisting of one dose of fudarabine, amsacrine and ara-C for four days) will be administered followed by reduced-intensity conditioning regimen (RIC) in the setting of allogeneic stem cell transplantation (SCT). The aim of the study is to explore the antileukemic, immunosuppressive effects and toxicity and safety of clofarabine in combination with ara-C in the setting of RIC allogeneic transplantation compared with the FLAMSA-protocol for patients with high-risk acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS).

ClAraC or FLAMSA Followed by Stem Cell Transplantation to Treat High Risk AML or Advanced MDS

Randomized, Multi-centre, Phase II Trial to Compare the Event-Free Survival of Clofarabine / Ara-C (ClAraC) or of FLAMSA Treatment in Patients With High Risk AML or Advanced MDS Scheduled for Allogeneic Stem Cell Transplantation

Genzyme, a Sanofi Company

Hannover Medical School

Director of the Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation

Neoplasm Metastasis

Daunorubicin

Antiviral Agents

Immunosuppressive Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Subjects are eligible to receive up to 2 inductions and up to 2 consolidations with CPX-351. The number of inductions and consolidations a subject received depended on response.

Subjects are eligible to receive up to 2 inductions and up to 2 consolidations with cytarabine and daunorubicin given as a 7 + 3, or 5 days of continuous infusion of cytarabine and 2 days of daunorubicin (5+2, second induction, consolidation courses) therapy. The number of inductions and consolidations a subject received depended on response.

First induction: 100 units/m2 by 90-minute IV infusion on Days 1, 3, 5. Second induction: 100 units/m2 by 90-minute IV infusion on Days 1 and 3. Consolidation therapy: 65 units/m2 by 90-minute IV infusion on Days 1 and 3.

CPX-351

First induction: 7+3 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 7 by continuous infusion, and daunorubicin at a dose of 60 mg/m2/day on Days 1, 2, and 3.

Second induction: 5+2 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 5 by continuous infusion and daunorubicin at a dose of 60 mg/m2/day on Days 1 and 2.

Consolidation therapy: 5+2 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 5 by continuous infusion, and daunorubicin at a dose of 60 mg/m2/day on Days 1 and 2.

7+3 (cytarabine and daunorubicin)

To confirm the efficacy of CPX-351 compared to 7+3 as first line therapy in elderly patients (60-75 yrs) with high risk (secondary) Acute Myeloid Leukemia. The primary efficacy endpoint will be overall survival.

Phase III Study of CPX-351 Versus 7+3 in Patients 60-75 Years Old With Untreated High Risk (Secondary) Acute Myeloid Leukemia

Phase III, Multicenter, Randomized, Trial of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection Versus Cytarabine and Daunorubicin in Patients 60-75 Years of Age With Untreated High Risk (Secondary) AML

Overall survival was measured from the date of randomization to death from any cause, subjects not known to have died by the last follow-up were censored on the date they were last known to be alive.

All randomized subjects were assessed for event-free survival (EFS). EFS was defined as the time from study randomization to the date of induction treatment failure (persistent disease), relapse from CR or CRi or death from any cause, whichever came first. Subjects alive and not known to have any of these events were censored on thee date they were last examined on study.

Only subjects achieving CR or CRi were assessed for remission duration.

All randomized subjects with at least 1 evaluable postrandomization bone marrow assessment performed on or after Day 14 after the last induction were assessed for MLFS.

The number and percentage of subjects transferred for HSCT after induction treatment was recorded.

The Leukemia and Lymphoma Society

Jazz Pharmaceuticals

Safety Population: All randomized participants who received at least one dose of study treatment.

Arm A (CPX-351)

Arm B (7+3)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Associate Director, Clinical Trial Disclosure & Transparency

Intent-to-Treat (ITT) Population: All participants randomized in the study.

Overall Survival

Proportion of Subjects With a Response

Event-free Survival

Remission Duration

Rate of Achieving Morphologic Leukemia-free State

Proportion of Subjects Receiving a Stem Cell Transplant

Overall Study

- Participants will complete baseline self-report assessments at the time of informed consent

Participants assigned to specialty palliative care will be cared for by both oncology and palliative care clinicians during their hospital stays for AML.

Specialty Palliative Care

Participants assigned primary palliative care will be cared for by oncology clinicians who have been trained in palliative care during the hospital stays for AML.

Primary Palliative Care

Areej El-Jawahri, MD

Porsha L Lark, MS, MPH

Dio Kavalieratos, MD

Martha Arellano, MD

Larry Cripe, MD

James Cleary, MD

Corey Tapper, MD

B. Douglas Smith, MD

Jennifer Temel, MD

Oreofe Odejide, MD, MPH

James Tulsky, MD

Mark Litzow, MD

Jacob Strand, MD

Laura Hanson, MD, MPH

William Wood, Jr., MD

Thomas LeBlanc, MD

Wil Santivasi, MD

Selina Luger, MD

Kathryn McGrath, MD

This research study is evaluating whether primary palliative care is an alternative strategy to specialty palliative care for improving quality of life, symptoms, mood, coping, and end of life outcomes in patients with acute myeloid leukemia (AML).

Patients with newly diagnosed AML confront a sudden and life-threatening diagnosis, requiring an immediate disruption of their life and an urgent hospitalization to begin therapy. During their hospitalization for chemotherapy, patients with AML often experience difficult physical symptoms that negatively impact their quality of life and physical function. Patients with AML also experience significant psychological distress as they combat the abrupt onset of illness, uncertainty regarding their prognosis, physical and social isolation during hospitalization, and complete loss of independence. The abrupt onset of these symptoms can be distressing to both the patient and their family and friends (also called "caregivers").

Research has shown that early involvement of a team of clinicians specializing in lessening (or "palliating") these physical and emotional symptoms and helping patients and their caregivers cope with AML improves their quality of life and experience with their illness. This team is called "specialty palliative care" and consists of physicians and advanced practice providers who work closely and collaboratively with the oncology team to care for patients and caregivers. Research has also shown that training oncology clinicians to incorporate palliative care skills into their practice, called "primary palliative care," is an alternative strategy to having specialty palliative care clinicians care for patients with leukemia.

The purpose of this study is to determine whether specialty palliative care or primary palliative care is the best way to improve the quality of life and experience of patients with AML and their caregivers. This study will randomly assign hospitals to deliver either specialty palliative care or primary palliative care for patients with AML. Participants in this study will receive either specialty or primary palliative care during their hospital stays based upon which strategy their hospital has been assigned to. Participants assigned to specialty palliative care will be care for by both oncology and palliative care clinicians during their hospital stays for AML. Participants assigned to primary palliative care will be cared for by oncology clinicians who have been trained in palliative care during their hospital stays for AML.

Specialty Compared to Oncology Delivered Palliative Care for Patients With Acute Myeloid Leukemia

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 Sponsor Investigator or designee. 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.

Compare patient prognostic understanding between those receiving primary palliative care and specialty palliative care based on the Prognostic Awareness Impact Scale (PAIS). The PAIS items that focus on the likelihood of cure will be used to compare prognostic understanding. Patients will report the likelihood of cure of their leukemia on a Likert's scale. Prognostic understanding will be dichotomized into likely cure versus. unlikely cure and compared between the two groups.

Compare patient coping between those receiving primary palliative care versus specialty palliative care using the Brief Cope. Higher scores on the domains of the Brief Cope indicate higher use of coping strategies.

Compare hospitalization in the last 30 days of life between those receiving primary palliative care versus specialty palliative care.

Compare intensive care unit admissions in the last 30 days of life between those receiving primary palliative care versus specialty palliative care.

Compare hospice utilization between those receiving primary palliative care versus specialty palliative care.

Compare hospice length of stay between those receiving primary palliative care versus specialty palliative care.

Compare patient symptom burden between those receiving primary palliative care versus specialty palliative care using the revised Edmonton Symptom Assessment Scale (ESAS-R).

Higher scores on ESAS-R (range 0 - 100) indicate greater symptom burden.

Compare patients' perception of patient-centeredness of care between those receiving primary palliative care versus specialty palliative care using the Patient Perception of Patient-Centeredness of Care (PPPC).

Higher scores indicate greater satisfaction with care.

Compare caregiver-reported end-of-life (EOL) communication between those receiving primary palliative care versus specialty palliative care measured by the Prognostic Awareness Impact Scale (PAIS). The PAIS includes an item that measures patient self-report of communication about their wishes if they were dying (yes vs. no).

Compare caregiver prognostic understanding between those receiving primary palliative care versus specialty palliative care based on the Prognositic Awareness Impact Scale (PAIS). PAIS items that focus on likelihood of cure will be used to compare prognostic understanding.

Compare caregiver coping between those receiving primary palliative care versus specialty palliative care using the Brief COPE. Higher scores on the domains of the Brief Cope indicate higher use of coping strategies.

Establish that primary palliative care is non-inferior to specialty palliative care in patient-reported quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leukemia) over 12 weeks.

Higher scores on FACT-Leukemia (range 0-176) indicate a better QOL.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to patient-reported quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leukemia).

Assess whether primary palliative care is non-inferior to specialty palliative care with depression symptoms as measured by the Hospital Anxiety and Depression Scale (HADS).

Higher scores on HADS depression subscale (range 0-21) indicate greater depression symptoms.

Assess whether primary palliative care is non-inferior to specialty palliative care with anxiety symptoms as measured by the Hospital Anxiety and Depression Scale (HADS).

Higher scores on HADS anxiety subscale (range 0-21) indicate greater anxiety symptoms.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to post-traumatic stress (PTSD) symptoms as measured by the Post-Traumatic Stress Checklist-Civilian version.

Higher scores on the Post-Traumatic Stress Checklist (range 17-85) indicate greater PTSD symptoms.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to patient reported end-of-life (EOL) communication measured by the Prognostic Awareness Impact Scale (PAIS).

The PAIS includes an item that measures patient self-report of communication about their wishes if they were dying (yes vs. no).

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to chemotherapy administration in the last 30 days of life based on documentation from the Electronic Health Record.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to caregiver quality of life measured by the Caregiver Oncology QOL Questionnaire (CARGOQOL).

Higher scores on CARGOQOL (range 0-100) indicate better QOL.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to caregiver burden measured by the Caregiver Reaction Assessment (CRA).

Higher scores on the CRA (range 24-120) indicate greater caregiving burden.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to caregiver depression symptoms measured by the Hospital Anxiety and Depression Scale (HADS).

Higher scores on HADS depression subscale (range 0-21) indicate greater depression symptoms.

Assess whether primary palliative care is non-inferior to specialty palliative care with respect to caregiver anxiety symptoms measured by the Hospital Anxiety and Depression Scale (HADS).

Higher scores on HADS anxiety subscale (range 0-21) indicate greater anxiety symptoms.

Patient-Centered Outcomes Research Institute

Massachusetts General Hospital

Principal Investigator

Venetoclax

Azacitidine

Lenograstim

Homoharringtonine

Aclarubicin

This cohort will determine the safety and efficacy of venetoclax, azacitidine combined with HAAG regimen in newly diagnosed intermediate and high-risk AML patients.

Venetoclax:100mg, qd, d1;200mg, qd, d2;400 mg, qd, d3\~10, per os; Azacitidine:75mg/m2/d, d1\~7, subcutaneous injection; Homoharringtonine:1mg/d, d4\~10, intravenous infusion; Aclarubicin:10mg/d, d4\~7, intravenous infusion; Cytarabine:10mg/m2,q12h,d4\~10, subcutaneous injection; Granulocyte colony-stimulating factor (G-CSF): 50-300μg/d (when WBC counts are less than 20×10\^9/L ),subcutaneous injection;

venetoclax, azacitidine and HAAG regimen

Xiaowen Tang, Ph.D

Depei Wu, Ph.D

The purpose of this study is to evaluate the efficacy and safety of VA combined with HAAG in the induction treatment of newly diagnosed acute myeloid leukemia.

This is a single-center, single-arm, prospective clinical study in newly diagnosed intermediate and high-risk AML patients. The patients will receive venetoclax, azacitidine combined with HAAG regimen in the induction treatment.

Study of VA Combined With HAAG Regimen in Newly Diagnosed Intermediate and High-risk AML Patients

A Single-center, Single-arm, Prospective Clinical Study on the Efficacy and Safety of Venetoclax and Azacitidine Combined With HAAG in the Induction Treatment of Intermediate and High-risk Acute Myeloid Leukemia

CRc includes complete response CR and CRi; CR was defined as \< 5% bone marrow blasts in an aspirate with spicules, no blasts with Auer rods or persistence of extramedullary disease, and independent of transfusions; CRi: was defined as\<5% bone marrow blasts, either ANC\<1×10\^9/L or platelets\<100×10\^9/L, transfusion independence but with persistence of cytopenia.

PR was defined as decrease of at least 50% in the percentage of blasts to 5-25% in the bone marrow aspirate and the normalization of blood counts.

adverse events are evaluated with CTCAE V5.0.

time from clinical CRc (CR and CRi) to the first relapse or death

time from the first day of treatment to death or lost to follow-up for any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nonmyeloablative Preparative Regimen Using Mylotarg for Patients With High Risk Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML) and Myelodysplastic Syndrome (MDS)	NCT00038805	Leukemia	Mylotarg	55 Years - 75 Years	M.D. Anderson Cancer Center
ClAraC or FLAMSA Followed by Stem Cell Transplantation to Treat High Risk AML or Advanced MDS	NCT01423175	Acute Myeloid L... MDS	Clofarabine, ar... FLAMSA	18 Years -	Hannover Medical School
Phase III Study of CPX-351 Versus 7+3 in Patients 60-75 Years Old With Untreated High Risk (Secondary) Acute Myeloid Leukemia	NCT01696084	High Risk Acute...	CPX-351 7+3 (cytarabine...	60 Years - 75 Years	Jazz Pharmaceuticals
Specialty Compared to Oncology Delivered Palliative Care for Patients With Acute Myeloid Leukemia	NCT05237258	Relapsed Adult ... Primary Refract... High Risk Acute...	Specialty Palli... Primary Palliat...	18 Years - 120 Years	Massachusetts General Hospital
Study of VA Combined With HAAG Regimen in Newly Diagnosed Intermediate and High-risk AML Patients	NCT06394011	Intermediate Ri... High Risk Acute...	venetoclax, aza...	18 Years - 65 Years	The First Affiliated Hospital of Soochow University
Specialty Compared to Oncology Delivered Palliative Care for Patients With Acute Myeloid Leukemia	NCT05237258	Relapsed Adult ... Primary Refract... High Risk Acute...	Specialty Palli... Primary Palliat...	18 Years - 120 Years	Massachusetts General Hospital

Spots Global Cancer Trial Database for high risk acute myeloid leukemia