Clinical Trials /

Study Evaluating Efficacy and Safety of CPI-613 in Combination With HD Cytarabine and Mitoxantrone Compared to HD Cytarabine and Mitoxantrone and Control Sub-groups: MEC and FLAG in Older Patients With R/R AML

NCT03504410

Description:

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 and control sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and Filgrastim (FLAG) 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 or other control sub groups.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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: 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)

Clinical Trial IDs

  • ORG STUDY ID: AML003
  • NCT ID: NCT03504410

Conditions

  • Relapsed/Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
CPI-613 + High Dose Cytarabine and MitoxantroneCPI-613, CHAMCPI-613 + HD Cytarabine and Mitoxantrone
High Dose Cytarabine and MitoxantroneHAMHD Cytarabine and Mitoxantrone

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
CPI-613 + HD Cytarabine and MitoxantroneExperimentalCPI-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.
  • CPI-613 + High Dose Cytarabine and Mitoxantrone
HD Cytarabine and MitoxantroneActive ComparatorHigh 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.
  • High Dose Cytarabine and Mitoxantrone

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:50 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Remission (CR)
Time Frame:8 months
Safety Issue:
Description:Complete disappearance of all clinical evidence of disease

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:12 months
Safety Issue:
Description:the duration from the date of randomization to the date of death from any cause
Measure:CR+CRh
Time Frame:12 months
Safety Issue:
Description:Complete Remission + CR with partial hematological recovery (CRh)

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rafael Pharmaceuticals Inc.

Last Updated

February 7, 2020