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CPX-351 in Patients Treated for Higher-risk Myelodysplastic Syndromes Experiencing Hypomethylating Agent Failure.

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ClinicalTrials.gov Identifier: NCT04109690
Recruitment Status : Recruiting
First Posted : September 30, 2019
Last Update Posted : September 11, 2020
Sponsor:
Information provided by (Responsible Party):
Thomas Prebet, Yale University

Brief Summary:
The proposed study is of a Liposomal formulation of cytarabine and daunorubicin (CPX-351) in patients treated for higher-risk myelodysplastic syndromes (MDS) experiencing hypomethylating agent failure.

Condition or disease Intervention/treatment Phase
MDS Drug: CPX-351 Phase 1 Phase 2

Detailed Description:

Proposed is a two-phase study. The Phase I portion will confirm the tolerability and safety of CPX-351 chemotherapy. Patients who meet eligibility criteria will receive dose level 1 of CPX-351 (44mg/m2 of daunorubicin and 100mg/m2 of cytarabine) on 2 days (day 1 and day 5) of the cycle.

If less than 2 dose limiting toxicity (DLT) are observed in the first cohort of 6, we will increase level of exposure to Dose Level 2 by giving (44mg/m2 of daunorubicin and 100mg/m2 of cytarabine) on days 1, 3 and 5 of

  • If less than 2 DLTs are observed Dose Level 2 will become the Recommended Phase II dose (RP2D)
  • If 2 or more DLTs are observed Dose Level 1 will become the RP2D If 2 or more DLTs are observed in the first cohort of 6 patients, another 6 patients will be enrolled at dose level -1 (29mg/m2 of daunorubicin and 65mg/m2 of cytarabine) on day 1 and 5.
  • If less than 2 DLTs are observed Dose Level -1 will become the RP2D
  • If 2 or more patients experience a DLT at dose -1 the study will be stopped Patients failing to achieve a response after cycle 1 will be offered a second cycle of induction with for dose level 1 and 2 (44mg/m2 of daunorubicin and 100mg/m2 of cytarabine) on day 1 and 5 of induction 2. And for dose level-1, (29mg/m2 of daunorubicin and 65mg/m2 of cytarabine) on day 1 and 5 of induction 2.

Phase II: Once the RP2D is confirmed we will enroll 12 patients. If 3 or more responses are observed an additional 12 patients will be enrolled for a total of 24. If 7 out of 24 evaluable patients achieve response, an additional 24 patients will be enrolled for a total of 48 patients.

• If less than 3 responses are observed in the first 12 patients, the study will be terminated.

The outcomes presented in this protocol are associated with the Phase II of the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I-II Study of a Liposomal Formulation of Cytarabine and Daunorubicin (CPX-351) in Patients Treated for Higher-risk Myelodysplastic Syndromes Experiencing Hypomethylating Agent Failure.
Actual Study Start Date : December 30, 2019
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : April 30, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CPX-351
Phase I will evaluate the safety and tolerability of CPX-351 (44mg/m2 of daunorubicin and 100mg/m2 of cytarabine) administered on 2 days (day 1 and day 5) to determine the Phase II dose. Phase II will evaluate the efficacy of the RP2D.
Drug: CPX-351
Patients in both Phase I and II can receive a maximum of two induction and six consolidation cycles on an inpatient or outpatient basis per local hospital standard of care.




Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: Up to 24 months ]
    The Phase II primary objective is to determine the overall response rate (CR/CRi) of CPX-351 in MDS patients experiencing hypomethylation (HMA) failure.



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Ages Eligible for Study:   18 Years to 78 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a diagnosis of MDS o (according to World Health Organization 2016 classification) made prior to administration off HMA
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2
  • Patient must have recovered from toxicities of any prior treatment regimen (no CTCAE grading over 1 for non-hematological toxicities and a return to baseline for hematological values)
  • Patient is considered eligible for chemotherapy (at discretion of local investigator)
  • Patient must have been treated with a hypomethylating agent (+/- other agents) and

    • be treated for at least 4 cycles (16 weeks) and have a stable marrow disease (no response) or
    • progressed without prior response based on MDS International Working Group (IWG) 2006 response criteria or
    • relapsed after an initial response based on MDS IWG 2006 response criteria.
  • Adequate liver and renal function:

    • Estimated creatinine clearance above 40 ml/min
    • Total bilirubin ≤ 1.5 x the Upper Limit of Normal (ULN) or ≤ 3.0 x the ULN unless considered due to Gilbert's syndrome,
    • Alanine aminotransferase (ALT) (SGPT), and aspartate aminotransferase (AST) (SGOT) ≤ 2.5 x the ULN. For patients with hepatic leukemic involvement Alanine aminotransferase (ALT) (SGPT), and aspartate aminotransferase (AST) (SGOT) ≤ 5.0 x the ULN t
  • Able to understand and sign the written informed consent
  • Serum or urine pregnancy test (for female patients of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (HCG) negative at screening.
  • Males and female patients both of childbearing potential and at risk for pregnancy must agree to use two highly effective method(s) of contraception throughout the study and for 180 days after the last dose of CPX-351 whichever occurs later.
  • Female patients who are not of childbearing potential (i.e. meet at least 1 of the following criteria):

    • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    • Have medically confirmed ovarian failure;
    • Have achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.

Exclusion Criteria:

  • Any prior induction chemotherapy (defined as treatment with standard or high dose cytarabine in combination with an anthracycline and/or other agents)
  • Any investigational agent administered within a month prior to inclusion or within 5 half-lives of the investigational agent whichever is longer.
  • Promyelocytic acute leukemia and core binding factor acute leukemia.
  • Active Central nervous system (CNS) disease
  • Any severe chronic disease potentially interfering with the protocol including HIV infection, active or chronic hepatitis B or C. Testing will be completed during screening period.
  • Any significant social condition that could limit the understanding of the study or the compliance to the protocol including but not limited to severe or uncontrolled psychiatric illness.
  • Any sign of active uncontrolled disease including but not restricted to cardiac disease, infections and platelet refractoriness.
  • Any other malignancy with active treatment within the past 1 year other than basal cell skin cancer or carcinoma in situ of the cervix.
  • New York Heart Association (NYHA) grade 3 or 4 cardiac failure, or left ventricular ejection fraction (LVEF) below 50%
  • Patients who have received a cumulative dose of anthracyclines superior to a total of 300mg/m2 of daunorubicin in the absence of prior mediastinal radiation or 150mg/m2 if the patient had a prior mediastinal radiation
  • Oxygen dependency as defined by a chronic need of oxygen at least 2l/min for at least 6h a day.
  • Women who are pregnant, planning to become pregnant, or who are currently breastfeeding
  • Persistence of any clinically relevant (CTCAE grade 2 or above) toxicities from previous therapy
  • Any other condition that, according to the investigator, may forbid the administration of CPX-351
  • Hypersensitivity to cytarabine, daunorubicin or liposomal products
  • History of Wilson's disease or another copper-metabolism disorder
  • Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04109690


Contacts
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Contact: Tara McPartland, MSW, MPH (203) 737-7173 tara.mcpartland@yale.edu

Locations
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United States, Connecticut
Yale University; Smilow Cancer Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Laura Leary       laura.leary@yale.edu   
Principal Investigator: Thomas Prebet, MD, PHD         
Sponsors and Collaborators
Thomas Prebet
Investigators
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Principal Investigator: Thomas Prebet, MD, PHD Yale University
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Responsible Party: Thomas Prebet, Associate Professor, Department of Hematology, Yale University
ClinicalTrials.gov Identifier: NCT04109690    
Other Study ID Numbers: 2000024262
First Posted: September 30, 2019    Key Record Dates
Last Update Posted: September 11, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Thomas Prebet, Yale University:
MDS
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms