CPX-351 in Higher Risk Myelodysplastic Syndromes

CPX-351 in Higher Risk Myelodysplastic Syndromes: a Phase I/ II Study as First Line or After Hypomethylating-agents Failure

Study of the efficacy of CPX-351 treatment in patients with higher risk myelodysplastic syndromes : as first line treatment or after hypomethylating agents failure

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: CPX-351 in cohort A; Drug: CPX-351 in cohort B

Detailed Description

A phase I/II study of the efficacy of CPX-351 treatment in patients with higher risk myelodysplastic syndromes : as first line treatment or after hypomethylating agents failure.

CPX-351 is an advanced liposomal formulation of daunorubicin and cytarabine encapsulated at a 1:5 ratio.

Patients will receive induction treatment with CPX-351. Patients in response (complete response (CR), complete response with incomplete hematologic improvement (CRi), partial response (PR)) after induction will receive monthly courses of consolidation therapy with CPX-351.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU d'Amiens - Service d'hématologie clinique et thérapie cellulaire
  • Angers, France, 49933
    • CHU D'ANGERS - Service des Maladies du Sang
  • Argenteuil, France, 95107
    • Centre hospitalier Victor Dupouy - Service d'Hématologie
  • Besançon, France, 25030
    • CHU de Besançon - Hôpital Jean Minjoz - Service d'hématologie clinique
  • Grenoble, France, 38043
    • CHU de Grenoble - Clinique Universitaire d'hématologie
  • Le Mans, France, 72037
    • CH Le Mans - Service d'onco-hématologie
  • Limoges, France, 87042
    • CHRU de Limoges - Hôpital Dupuytren - Service d'hématologie clinique et thérapie cellulaire
  • Marseille, France, 13273
    • Institut Paoli Calmettes - Unité d'hématologie 3
  • Nantes, France, 44093
    • CHU Hôtel Dieu - Service d'Hématologie Clinique
  • Nice, France, 06202
    • CHU-Hôpital Archet I - Service d'Hématologie Clinique
  • Paris, France, 75010
    • Hôpital Saint Louis - Service hématologie séniors
  • Pessac, France, 33604
    • CHU de Bordeaux - Hôpital de Haut-Lévêque - Service des maladies du sang
  • Poitiers, France, 86021
    • CHU de Poitiers - Service d'onco-hématologie et thérapie cellulaire
  • Rennes, France, 35033
    • Hôpital Pontchaillou - Service d'hématologie clinique
  • Saint Priest-en-Jarez, France, 42270
    • Institut de Cancérologie Lucien Neuwirth - Hématologie Clinique - Thérapie Cellulaire
  • Toulouse, France, 31059
    • IUCT-oncopole - Fédération Hématologie - Médecine Interne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Myelodysplastic syndrome (WHO 2016 classified) including CMML (even if white blood cell count (WBC) > 13000/mm3).
• For COHORT A: untreated patients except by erythropoiesis stimulating agents, Lenalidomide or non-chemotherapy during a phase of lower risk MDS; For COHORT B: absence of response (CR, CRi, PR or HI according to international working group (IWG) 2006 for MDS) after a minimum of 6 cycles of single hypomethylating agent or relapse after a response.
• For COHORT A: less than 20% of marrow blasts. For COHORT B: less than doubling of marrow blasts compared with onset of hypomethylating agent.
• Classical international prognostic scoring system (IPSS) int-2 or high risk score.
• For COHORT A and B : age between 18 and 70 years
• For COHORT A: Performance status (ECOG grading) ≤ 1; For COHORT B: Performance status ≤ 2.
• Eligible for standard intensive chemotherapy.
• Absence of concomitant severe cardiovascular disease which would make intensive chemotherapy impossible, i.e. arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, reduced left ventricular function assessed by multigated acquisition (MUGA) scan or echocardiogram.
• Patient must have adequate organ function as indicated by the following laboratory values: Renal: Serum creatinine < 2 mg/dl or calculated creatinine clearance ≥ 60 mL/min by MDRD (modification of the diet in renal disease) or CKD-EPI (chronic kidney disease epidemiology collaboration) equation for patients with creatinine levels > 1.5xULN ; Hepatic: Serum total bilirubin ≤ 2.5xULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL, aspartate aminotransferase (ALT) and alanine aminotransferase (ALT) ≤ 2.5xULN, Alkaline Phosphatase ≤ 5xULN (if > 2.5xULN, then liver fraction should be ≤ 2.5xULN).
• Patients not known to be refractory to platelet transfusions.
• Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles. Female patient is not actively breastfeeding at the time of study entry.
• Female patients are either post-menopausal, free from menses for > 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agree to abstain from becoming pregnant throughout the study, starting with Visit 1. Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 6 months (females and males) following the last dose of CPX-351.
• Male patients agree to use an adequate method of contraception for the duration of the study. Men should be advised not to father a child while receiving CPX-351 and for 6 months post study.
• Patients are available for regular blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.
• Patients have the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.

Exclusion Criteria:

• Active and uncontrolled infection.
• Last dose of hypomethylating agent given more than 4 months before entering the trial.
• Uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
• Current participation or participation in a study with an investigational compound or device within 30 days of initial dosing with study drug.
• Known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
• Clinically active hepatitis B or hepatitis C infection.
• Known allergy or hypersensitivity to any component of CPX-351.
• "Currently active" second malignancy, other than non-melanoma skin cancer and in situ carcinoma of the cervix.
• Subjects with a history of Wilson's disease or other copper-related disorder.
• Treatment with growth factors such as erythropoietin alfa (EPO) or granulocyte colony-stimulating factor (G-CSF) or cytotoxic and non-cytotoxic agents (including low dose oral chemotherapy with the exception of hydroxyurea) in the 30 days before inclusion.
• Treatment with systemic steroids that has not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
• Clinical evidence of central nervous system leukemia.
• Pregnancy or breastfeeding during the projected duration of the study.
• Absence of social security.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A - First line treatment; Untreated patients	Drug: CPX-351 in cohort A; Treatment by CPX-351 via intravenous infusion over 90 minutes. Induction treatment with CPX-351 100 Units/m²/D on days 1, 3 and 5. If response after this induction treatment, 4 courses of consolidation therapy with CPX-351 100 Units/m²/D on day 1. If no response after this induction treatment, a second induction course of CPX-351 100 Units/m²/D on days 1 and 3. If response is achieved after this salvage course, 3 courses of consolidation therapy with CPX-351 100 Units/m²/D on day1.
Experimental: Cohort B - Hypomethylating failure; Patients in absence of response after hypomethylating agents treatment	Drug: CPX-351 in cohort B; Treatment by CPX-351 via intravenous infusion over 90 minutes. This will be a dose-finding study : CPX-351 100 Units/m²/D on days 1, 3 and 5 or CPX-351 100 Units/m²/D on days 1 and 3 or CPX-351 60 Units/m²/D on days 1 and 3. In response after induction treatment, 4 monthly courses of consolidation therapy with CPX-351 at the same dose on day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate (CR, CRi, PR)	Response to induction therapy	28 to 42 days after induction

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (CR, CRi, PR, HI)	Response to induction therapy	28 to 42 days after induction
Event free survival	Event free survival	42 months
Response duration	Duration of the response to induction therapy	42 months
Overall survival	Overall survival	42 months
Toxicity profile - Duration of cytopenias	Duration of cytopenias	42 months
Toxicity profile - life threatening or fatal cytopenias	Number of life threatening or fatal cytopenias	42 months
Toxicity profile - hospitalization	Time spent in hospital for induction and consolidation cycles	42 months
Evaluation of minimal residual disease (MRD) after induction and after the last consolidation	Evaluation of MRD by flow cytometry	42 months
Evaluation of minimal residual disease (MRD) after induction and after the last consolidation	Evaluation of variant allelic frequency (VAF) of Baseline mutations	42 months
Soluble Fms-like tyrosine kinase 3 ligand concentration (sFLc) in plasma during induction	sFLc plasma level assessments at day 1 of induction just before starting treatment, and then at days 8, 15 and 22 of induction	42 months

Collaborators and Investigators

• Sponsor: Groupe Francophone des Myelodysplasies
• Investigators: Principal Investigator: Pierre PETERLIN, MD, CHU Nantes

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2020
• Primary Completion (Actual): August 27, 2021
• Study Completion (Actual): July 6, 2022

Study Registration Dates

• First Submitted: February 12, 2020
• First Submitted That Met QC Criteria: February 14, 2020
• First Posted (Actual): February 18, 2020

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 6, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: MDS high risk
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia
• Other Study ID Numbers: GFM-CPX-MDS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No