CPX-351 and Gemtuzumab Ozogamicin in Treating Patients With Relapsed Acute Myeloid Leukemia

November 17, 2023 updated by: Jonsson Comprehensive Cancer Center

A Phase Ib Trial With Dose Expansion Evaluating CPX-351 Plus Gemtuzumab Ozogamicin for Relapsed Acute Myelogenous Leukemia

This phase Ib trial studies the best dose of gemtuzumab ozogamicin when given together with CPX-351 in treating patients with acute myeloid leukemia that has come back after it was previously in remission. CPX-351 is a chemotherapy, which works 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. Gemtuzumab ozogamicin is a monoclonal antibody, called gemtuzumab, linked to chemotherapy called calicheamicin. Gemtuzumab attaches to CD33 (transmembrane receptor) positive cancer cells in a targeted way and delivers ozogamicin to kill them. Giving CPX-351 and gemtuzumab ozogamicin may work better in treating patients with acute myeloid leukemia, compared to giving only one of these therapies alone.

Study Overview

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the phase II dose of the combination liposome-encapsulated daunorubicin-cytarabine (CPX-351) plus gemtuzumab ozogamicin (GO) by means of estimating maximum tolerated dose (MTD) in participants with relapsed acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To estimate the remission rate (complete remission plus complete remission with incomplete hematologic recovery) of participants in the MTD cohort who receive CPX-351 plus GO.

II. To evaluate CPX-351 plus GO as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT) in participants with relapsed AML.

III. To estimate the duration of remission. IV. To evaluate for toxicity by means of Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

V. To evaluate for the development of veno-occlusive disease at any point during the study in participants treated with CPX-351 plus GO.

VI. To evaluate time to return of normal hematopoiesis after induction therapy. VII. To evaluate 30- and 60-day survival.

EXPLORATORY OBJECTIVES:

I. To evaluate if there is a difference in remission rate based on CD33 splicing single nucleotide polymorphism (SNP) genotype (CC, TC, or TT) in participants receiving CPX-351 plus GO.

II. To evaluate the impact that leukemia cell multidrug resistance activity have on achieving remission after treatment with CPX-351 plus GO.

III. To evaluate the possible associations of participant constitutional genotype, leukemia genotype, and response to therapy.

IV. To evaluate the possible associations of participant ribonucleic acid (RNA) expression, leukemia RNA expression, and response to therapy.

OUTLINE: This is a dose-escalation study of gemtuzumab ozogamicin when given in combination with liposome-encapsulated daunorubicin-cytarabine.

INDUCTION: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV) over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 7 in the first cohort of study participants, days 4 and 7 in the second cohort of study participants, or days 1, 4, and 7 in the third cohort of study participants, in the absence of disease progression or unacceptable toxicity. The dose expansion cohort will receive the above treatment schedule that is determined to be the maximum tolerated dose.

CONSOLIDATION: Patients who achieve complete remission (CR)/CR with incomplete hematologic recovery (CRi) receive consolidation therapy at the discretion of the treating physician and/or proceed to allogeneic HSCT.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • California
      • Los Angeles, California, United States, 90095
        • UCLA / Jonsson Comprehensive Cancer Center
      • Orange, California, United States, 92868
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
      • Sacramento, California, United States, 95817
        • University of California Davis Comprehensive Cancer Center
      • San Diego, California, United States, 92103
        • University Of California San Diego
      • San Francisco, California, United States, 94115
        • UCSF Medical Center-Mount Zion

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Bone marrow blasts >= 5% that develops after remission, no restriction on prior number of relapses or regimens
  • Eastern Cooperative Oncology Group (ECOG) 0-2
  • At least a 3-month duration of remission prior to relapse
  • Participants with relapse after allogeneic transplantation are included
  • Up to 1 cycle of hypomethylating agent monotherapy at time of relapse is allowed, must be discontinued at least 14 days prior to start of salvage induction
  • Serum total bilirubin =< 2.0 mg/dL, unless considered due to Gilbert?s disease or leukemia involvement
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 times the upper limit of normal, unless considered due to leukemia involvement
  • Alkaline phosphatase =< 3 times the upper limit of normal, unless considered due to leukemia involvement
  • Serum creatinine =< 2.0 mg/dL, or creatinine clearance > 40 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR)
  • Ability to give full informed consent on their own
  • Females of reproductive potential (postmenopausal for less than 24 consecutive months) must have a negative pregnancy

Exclusion Criteria:

  • Currently receiving targeted therapy for FLT3 (cytokine receptor tyrosine kinase class III), IDH1, or IDH2 (isocitrate dehydrogenase, 1, 2) mutations and intent to continue use; prior use of targeted therapy for such mutations is allowed, but agents should be discontinued 1 week prior to enrollment
  • Acute promyelocytic leukemia
  • Second malignancy that would limit survival by less than 2 years
  • New York Heart Association class III or VI
  • Left ventricular ejection fraction < 50%
  • History of coronary stent placement that requires mandatory continuation of dual-antiplatelet therapy
  • History of Wilson?s disease or other copper handling disorders
  • Hypersensitivity to cytarabine, daunorubicin, or liposomal products
  • Active invasive fungal infection
  • Active bacterial or viral infection manifesting as fevers or hemodynamic instability within the past 72 hours
  • Lifetime cumulative daunorubicin-equivalent anthracycline dose > 368 mg/m^2

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (CPX-351, gemtuzumab ozogamicin)

INDUCTION: Patients receive liposome-encapsulated daunorubicin 44mg/m2 - cytarabine 100mg/m2 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin 3 mg/m2 (max 4.5 mg) IV over 120 minutes on day 7, or days 4 and 7, or days 1, 4, and 7 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve CR/CRi receive consolidation therapy at the discretion of the treating physician and/or proceed to allogeneic HSCT.

Given IV
Other Names:
  • CPX-351
  • Cytarabine-Daunorubicin Liposome for Injection
  • Liposomal AraC-Daunorubicin CPX-351
  • Liposomal Cytarabine-Daunorubicin
  • Liposome-encapsulated Combination of Daunorubicin and Cytarabine
  • Vyxeos
Given IV
Other Names:
  • Mylotarg
  • Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody
  • CDP-771
  • CMA-676
  • gemtuzumab
  • hP67.6-Calicheamicin
  • WAY-CMA-676

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose (MTD)
Time Frame: Up to day 42
MTD is defined as the cohort of participants one cohort below the cohort that develop dose-limiting toxicity (DLT) in at least 2 participants.
Up to day 42

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate (ORR)
Time Frame: Up to day 42
Objective response, including complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi), after induction therapy will be measured using the International Working Group (IWG) Response Criteria in acute myeloid leukemia (AML).
Up to day 42
Proportion of participants who go on to receive allogeneic hematopoietic cell transplantation (HSCT) after achieving CR/CRi
Time Frame: Up to 18 months
The proportion of patients who receive an allogeneic HSCT following a CR/CRi response will be reported along with an exact 95% confidence interval.
Up to 18 months
Duration of remission
Time Frame: Up to 18 months
Evaluated in participants that achieve CR/CRi, and defined as number of days that elapse from first day CR/CRi to the first day that bone marrow blasts >= 5%. The median duration of remission will be reported in patients who achieved CR/CRi, along with the corresponding range.
Up to 18 months
Incidence of toxicities
Time Frame: Up to day 42
Measured by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Up to day 42
Diagnosis of veno-occlusive disease (VOD)
Time Frame: Up to 18 months
The diagnosis of veno-occlusive disease is based on the Baltimore criteria: Bilirubin > 2.0 mg/dL, plus, painful hepatomegaly, ascites, and weight gain > 5% basal since initiating therapy with gemtuzumab ozogamicin (GO). The proportion of patients who develop VOD will be reported along with an exact 95% confidence interval.
Up to 18 months
Time to return of normal hematopoiesis
Time Frame: From day 1 of induction, assessed up to 18 months
Defined as the number of days from day 1 of induction to ANC (absolute neutrophil count) >= 1000/uL (upper limit) and platelet count >= 100,000/uL. Will be reported along with the corresponding range.
From day 1 of induction, assessed up to 18 months
Number of participants deceased at day 30 and day 60
Time Frame: At 30 and 60 days following the start of induction
Mortality is defined as death having occurred in any participant that receives at least one dose of experimental therapy. Kaplan-Meier methods will estimate the overall survival at day 30 and day 60 following the start of induction. The survival estimate at these two time points will be reported along with a 95% confidence interval.
At 30 and 60 days following the start of induction

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genotype at CD33 splicing single nucleotide polymorphism (SNP) RS12459419
Time Frame: Up to 18 months
Determined by whole exome sequencing and confirmatory genotyping.
Up to 18 months
Multidrug resistance activity of leukemia cell P-glycoprotein (Pgp)
Time Frame: Up to 18 months
Will be determined by the flow cytometry mean fluorescence intensity (MFI) of the efflux of the fluorescent dye DiOC2 (Diethyloxacarbocyanine iodide) (by malignant cells. Will be assessed by dye efflux assay as described by Walter et al. 2003.
Up to 18 months
Multidrug resistance activity of leukemia cell multidrug resistance protein 1 (MRD1)
Time Frame: Up to 18 months
Will be determined by the flow cytometry efflux MFI of the efflux of the fluorescent dye 5-carboxy-2?,7?-dichlorofluorescein diacetate (CDCF) by malignant cells. Will be assessed by dye efflux assay as described by Walter et al. 2003.
Up to 18 months
Exome sequencing analysis
Time Frame: Up to 18 months
Tumor deoxyribonucleic acid (DNA) and participant DNA will be measured via Illumina HiSeq3000 sequencing platform to evaluate for associations between participant constitutional genotype (buccal swab sample at enrollment), leukemia genotype (bone marrow aspirate at enrollment and upon relapse), and response to therapy.
Up to 18 months
Ribonucleic acid (RNA) sequencing analysis
Time Frame: Up to 18 months
Tumor RNA and participant RNA will be measured via RNA sequencing technique.
Up to 18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Caspian Oliai, MD, UCLA / Jonsson Comprehensive Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 18, 2019

Primary Completion (Actual)

October 25, 2023

Study Completion (Actual)

October 25, 2023

Study Registration Dates

First Submitted

April 3, 2019

First Submitted That Met QC Criteria

April 3, 2019

First Posted (Actual)

April 5, 2019

Study Record Updates

Last Update Posted (Actual)

November 18, 2023

Last Update Submitted That Met QC Criteria

November 17, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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