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Study Evaluating Efficacy and Safety of CPI-613 in Combination With HD Cytarabine and Mitoxantrone vs HD Cytarabine and Mitoxantrone in Older Patients With R/R AML

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ClinicalTrials.gov Identifier: NCT03504410
Recruitment Status : Recruiting
First Posted : April 20, 2018
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
Rafael Pharmaceuticals Inc.

Tracking Information
First Submitted Date  ICMJE April 12, 2018
First Posted Date  ICMJE April 20, 2018
Last Update Posted Date February 11, 2020
Actual Study Start Date  ICMJE November 12, 2018
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2018)
Complete Remission (CR) [ Time Frame: 8 months ]
Complete disappearance of all clinical evidence of disease
Original Primary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
Complete Remission (CR) [ Time Frame: 12 months ]
Change History Complete list of historical versions of study NCT03504410 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2020)
  • Overall Survival (OS) [ Time Frame: 12 months ]
    the duration from the date of randomization to the date of death from any cause
  • CR+CRh [ Time Frame: 12 months ]
    Complete Remission + CR with partial hematological recovery (CRh)
Original Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
  • Overall Survival (OS) [ Time Frame: 12 months ]
  • Complete remission + complete remission with partial hematologic recovery (CR +CRh) [ Time Frame: 12 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study Evaluating Efficacy and Safety of CPI-613 in Combination With HD Cytarabine and Mitoxantrone vs HD Cytarabine and Mitoxantrone in Older Patients With R/R AML
Official Title  ICMJE Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (Devimistat) in Combination With High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥50 Years) With Relapsed/Refractory Acute Myeloid Leukemia (AML)
Brief Summary A Phase III study to evaluate the safety and efficacy of CPI-613® (devimistat) in combination with High Dose Cytarabine and Mitoxantrone in comparison with high dose Cytarabine and Mitoxantrone in older patients with relapsed/refractory Acute Myeloid Leukemia. CPI-613® (devimistat) targets the altered energy metabolism and processes for production of ATP and essential bio-intermediates unique to and characteristic of most cancer cell types. The addition of CPI-613® (devimistat) to high dose cytarabine and mitoxantrone (CHAM) will improve the complete remission (CR) rate in patients 50 years or older with relapsed or refractory AML when compared to HAM alone.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Relapsed/Refractory Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: CPI-613 + High Dose Cytarabine and Mitoxantrone
    CPI-613 + High Dose Cytarabine and Mitoxantrone CPI-613: 2000mg/m2, 5 doses once a day, days 1-5 Cytarabine 1gm/m2, 5 doses every 12hrs starting day 3 through day 5 Mitoxantrone 6mg/m2, 3 doses, once a day following the first, third and fifth doses of Cytarabine
    Other Name: CPI-613, CHAM
  • Drug: High Dose Cytarabine and Mitoxantrone
    Cytarabine 1gm/m2, 5 doses every 12hrs starting day 3 through day 5 Mitoxantrone 6mg/m2, 3 doses, once a day following the first, third and fifth doses of Cytarabine
    Other Name: HAM
Study Arms  ICMJE
  • Experimental: CPI-613 + HD Cytarabine and Mitoxantrone

    CPI-613 + High Dose Cytarabine and Mitoxantrone

    CPI-613 at 2,000 mg/m2/day from day 1 to 5.

    Cytarabine at 1gm/m2 (5 doses), every 12 hours starting day 3. Mitoxantrone at 6gm/m2 (3 doses), everyday following the 1st, 2nd and 5th doses of Cytarabine.

    Intervention: Drug: CPI-613 + High Dose Cytarabine and Mitoxantrone
  • Active Comparator: HD Cytarabine and Mitoxantrone

    High Dose Cytarabine and Mitoxantrone

    Cytarabine at 1gm/m2 (5 doses), every 12 hours starting day 3. Mitoxantrone at 6gm/m2 (3 doses), everyday following the 1st, 3rd and 5th doses of Cytarabine.

    Intervention: Drug: High Dose Cytarabine and Mitoxantrone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 19, 2018)
500
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2023
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

INCLUSION CRITERIA:

  1. Patient has provided an informed consent prior to initiation of any study specific activities/procedures.
  2. Males and females age ≥ 50 years must have histologically documented AML that is relapsed from, or refractory to, prior standard therapies.
  3. Refractory is defined as failure to achieve CR or CRi following:

    1. Two standard dose Cytarabine based induction cycles or one HiDAC based cycle or,
    2. Persistent disease after one cycle of standard dose cytarabine (defined as no decrease in marrow blast percentage from diagnosis on Day 14 marrow) or,
    3. Persistent disease after at least 2 cycles of a hypomethylating agent (azacytidine or decitabine) with or without venetoclax
  4. Relapse is defined as development of recurrent AML (as described by Döhner et al, 2017)6 after CR or CRi has been achieved with a prior chemotherapy or after disease progression on a hypomethylating agent with or without venetoclax.
  5. ECOG PS 0-2
  6. Expected survival greater than 3 months.
  7. Women of child-bearing potential (i.e. women who are pre-menopausal or < 2 years post-menopausal or not surgically sterile) must practice a highly effective method of birth control consistent with local regulations regarding the use of birth control methods. Examples: use of oral, injected or implanted hormonal methods of contraception; placement of an intra uterine device (IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence during and for 6 months after the last administered dose of CHAM or HAM therapy, and must have a negative serum pregnancy test within 1 week prior to treatment initiation and at 1st day of each cycle and at the end of systemic exposure. (Note: pregnant patients are excluded because the effects of CPI-613® (devimistat) on a fetus are unknown).
  8. Fertile men who are sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during the study period and up to 6 months after completion of the study screening, unless documentation of infertility exists.
  9. Good state of mental health, ability to understand and willingness to sign the informed consent form (ICF).
  10. No radiotherapy, treatment with cytotoxic chemotherapy, treatment with biologic agents or any anti-cancer therapy within the 1 week prior to treatment with CPI-613® (devimistat). Hydroxyurea and oral tyrosine kinase (FLT3) or Isocitrate Dehydrogenase 1 and 2 (IDH1/2) inhibitors being used with Grade ≤ 2 toxicity can be taken until the day prior to starting study therapy. Previous exposure to a hypomethylating agent either alone or in combination with Venetoclax is allowed. Patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities with the exception of alopecia (returned to baseline status as noted before most recent treatment). Patients with persisting, non-hematologic, non-infectious toxicities from prior treatment Grade ≤ 2 are eligible but must be documented as such
  11. Laboratory values ≤ 2 weeks before dosing must be:

    • Adequate hepatic function (aspartate aminotransferase/serum glutamic-oxaloacetic transaminase [AST/SGOT] ≤ 5 x upper limit of normal [ULN], alanine aminotransferase/serum glutamic oxaloacetic transaminase [ALT/SGPT] ≤ 5 × ULN, bilirubin ≤ 1.5 × ULN).
    • Adequate renal function (serum creatinine clearance ≥ 60 mL/min per CockCroft-Gault formula).
    • Adequate coagulation (International Normalized Ratio [INR] must be < 1.7 unless on vitamin k antagonist anticoagulation).
  12. Left Ventricular Ejection Fraction (LVEF) by Transthoracic Echocardiogram (TTE) or Multigated Acquisition Scan (MUGA) or cardiac Magnetic Resonance Imaging (MRI), sufficient to safely administer mitoxantrone. Subjects must have an LVEF ≥ 45%.
  13. No marked baseline prolongation of QT/QTc interval (repeated exhibition of a QTc interval > 450 ms for male and > 470 ms for female patients).
  14. No history of additional risk factors for torsade de pointes (e.g. clinically significant heart failure, hypokalemia, immediate family history of Long QT Syndrome).
  15. Allow only patients who experienced relapse after 1 year from previous HiDAC treatment or who didn't receive HiDAC previously (Note: This inclusion applies only to South Korea).

EXCLUSION CRITERIA:

  1. Patients who have received cytotoxic chemotherapy treatment for their current relapsed or refractory AML. (Treatment with hypomethylating agents (decitabine or azacytidine) either alone or in combination with venetoclax is allowed. Targeted therapies including FLT3 or IDH1/2 inhibitors or Hydrea or venetoclax are allowed. Targeted therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy)
  2. Vulnerable adult and patient whose health conditions does not allow them to give their consent
  3. History or evidence of any other clinically significant disorder, condition or disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, symptomatic myocardial infection, uncontrolled cardiac arrhythmia, pericardial disease or heart failure New York Heart Association Class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients' risk for toxicity and in the opinion of the Investigator, would pose a risk to patient safety or interfere with the study evaluation, procedures or completion
  4. Patients with active Central Nervous System (CNS) involvement (leukemic infiltration, blast in the spinal fluid)
  5. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g. active peptic ulcer disease)
  6. Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of CHAM or HAM therapy (the teratogenic potential of CPI-613® (devimistat) is unknown). Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at Screening.
  7. Women of childbearing potential (i.e. women who are pre-menopausal or < 2 years postmenopausal or not surgically sterile) unwilling to practice a highly effective method of birth control consistent with local regulations regarding the use of birth control methods during treatment and for 6 months after completion of CHAM or HAM therapy for AML
  8. Male patients with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for 6 months after completion of CHAM or HAM therapy.
  9. Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of CHAM or HAM therapy with potential highest teratogenic risk.
  10. Known hypersensitivity to study treatment drugs or any of the excipient(s) contained in the drug formulation.
  11. Life expectancy less than 3 months.
  12. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients.
  13. Unwilling or unable to follow protocol requirements.
  14. Patients with large and recurrent pleural or peritoneal effusions requiring frequent drainage (e.g. weekly).
  15. Patients with any amount of clinically significant pericardial effusion that requires drainage.
  16. Evidence of ongoing, uncontrolled bacterial, viral or fungal infection.
  17. Patients with known human immunodeficiency virus infection.
  18. History of other malignancy within the past 5 years, with the following exception(s):

    1. Malignancy treated with curative intent and with no known active disease present for ≥ 5 years before enrolment and felt to be at low risk for recurrence by the treating physician
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of recurrent or residual disease
    3. Adequately treated cervical carcinoma in situ without evidence of disease
    4. Prostate cancer Stage 1
  19. Patients receiving any other standard or investigational treatment for AML, or any other investigational agent for any indication within the past 1 week prior to initiation of CPI-613® (devimistat) treatment (the use of Hydrea and/or venetoclax, oral tyrosine kinase inhibitors FLT3 or IDH 1/2 inhibitors is allowed until the day prior to starting CHAM or HAM therapy. Previous exposure to a hypomethylating agent either alone or in combination with venetoclax is allowed).
  20. Patients who have received immunotherapy of any type within the past 1 week prior to initiation of CPI-613® (devimistat) treatment.
  21. Requirement for immediate palliative treatment of any kind including minor surgery.
  22. Patients who have received a chemotherapy regimen with autologous stem cell support (bone marrow transplantation) within 6 months.
  23. Patients who have had allogenic bone marrow transplantation within the last 6 months. Patients who have had an allogenic transplant more than 6 months ago are eligible provided they have no graft vs host disease.
  24. Cytarabine contraindications

    • Hypersensitivity to the cytarabine or to any of the excipients of cytarabine injection.
    • Anemia, leucopenia and thrombocytopenia of non-malignant aetiology (e.g bone marrow aplasia); unless the clinician feels that such management offers the most hopeful alternative for the patient.
    • Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation.
  25. Mitoxantrone contraindications

    • Mitoxantrone Sterile Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to mitoxantrone hydrochloride, other anthracyclines or any of its components. Use in patients with profound bone marrow suppression is a relative contraindication depending on the clinical circumstances.
    • Mitoxantrone Sterile Concentrate should not be used during pregnancy or lactation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sanjeev Luther 585-978-1351 sanjeev.luther@rafaelpharma.com
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   France,   Korea, Republic of,   Poland,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03504410
Other Study ID Numbers  ICMJE AML003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Rafael Pharmaceuticals Inc.
Study Sponsor  ICMJE Rafael Pharmaceuticals Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jorge Eduardo Cortes, MD Augusta University
PRS Account Rafael Pharmaceuticals Inc.
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP