Clinical trial NCT03504410: Efficacy/Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. in Older Patients With R/R AML
Official title: Phase 3 Multicenter Randomized Trial to Evaluate Efficacy and Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. Therapy and Control Sub-groups in Older Patients With R/R AML
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Relapsed/Refractory Acute Myeloid Leukemia
Lead sponsor: Cornerstone Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-04-20
Enrollment: 200
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Detailed description: Subjects were randomized in 1:1 allocation ratio by IWRS according to the stratification factors. However, the control sub-groups (MEC and FLAG) were capped at 100 (50 per sub-group).

Subjects in both Arm 1 and Arm 2 were planned to receive induction cycle 1 treatment for at least 14 days. Subjects will receive follow-up therapy based on results of the bone marrow aspirate, and CR/complete remission with incomplete recovery (CRi) status.

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. At least one cycle of any anthracycline, cytarabine or fludarabine containing induction regimen or persistence of disease on a nadir marrow following at least one cycle of any anthracycline, cytarabine or fludarabine containing induction regimen
   2. 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 control sub-groups (MEC and FLAG), 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 for R/R AML within the 1 week prior to treatment with CPI-613® (devimistat). Hydroxyurea and/or venetoclax and oral tyrosine kinase (FLT3) or Isocitrate Dehydrogenase 1 and 2 (IDH1/2), BCL-2 or hedgehog inhibitors being used with Grade ≤ 2 toxicity can be taken until the day prior to starting of CHAM or HAM therapy or control sub-groups (MEC and FLAG). Previous exposure to a hypomethylating agent either alone or in combination with Isocitrate Dehydrogenase 1 and 2 (IDH1/2), BCL-2 or hedgehog inhibitors are allowed until the day prior to starting of CHAM or HAM therapy and control sub-groups (MEC and FLAG). 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 \> 480 ms for both male and 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 are allowed until the day prior to starting of CHAM or HAM therapy and control sub-groups (MEC and FLAG). Targeted therapies including FLT3 or IDH1/2 inhibitors and/or Hydrea and/or venetoclax are allowed. Targeted therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy or control sub-groups (MEC and FLAG)
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 or control sub-groups, MEC and FLAG (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 or control sub-groups, MEC and FLAG 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 or control sub-groups, MEC and FLAG
9. Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of CHAM or HAM therapy or control sub-groups, MEC and FLAG 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 are allowed until the day prior to starting CHAM or HAM therapy or control sub-groups, MEC and FLAG. Previous exposure to a hypomethylating agent either alone or in combination with venetoclax are allowed until the day prior to starting of CHAM or HAM therapy and control sub-groups (MEC and FLAG))
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 of starting CHAM or HAM therapy or control sub-groups (MEC and FLAG)
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. (Note: Exclude only patients with active GVHD requiring therapy with immunosuppressive agents and not patients with stable GVHD not requiring immunosuppression.)
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
26. Strong CYP450 inducers should be prohibited
27. Etoposide contraindications

    •. Contraindicated in patients with a history of a severe hypersensitivity reaction to etoposide products
28. Fludarabine contraindications

    •. Contraindicated in those patients who are hypersensitive to this drug or its components
29. Filgrastim contraindications •. Contraindicated in patients with known hypersensitivity to E coli-derived proteins, Filgrastim, or any component of the product

Primary outcomes:
measure: Complete Remission (CR)
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Honor Health Research Institute
state: Arizona
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center (University of California Irvine)
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa-Holden Cancer Care Center
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Long Island City
country: United States
facility: Stony Brook University Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Dallas
country: United States
facility: University of Texas - Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Andrson Cancer Center
state: Texas
city: Temple
country: United States
facility: Baylor Temple (BSW)
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Albury
country: Australia
facility: Border Medical Oncology Research Unit
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle Hospital
state: New South Wales
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Graz
country: Austria
facility: Universitätsklinik für Innere Medizin
city: Salzburg
country: Austria
facility: Paracelsus Medical University
city: Wien
country: Austria
facility: Hanuschkrankenhaus der WGKK
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan
city: Brussels
country: Belgium
facility: Clinique Universitaire St Luc
city: Gent
country: Belgium
facility: UN Gent
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles - Hôpital André Mignot
state: Yvelines
city: Amiens
country: France
facility: CHU Amiens
city: Bobigny
country: France
facility: Service d'Hématologie Clinique, Hôpital Avicenne-APHP-Université Paris
city: Caen
country: France
facility: CHU de Caen
city: Grenoble Cedex 9
country: France
facility: Centre Hospitalier Universitaire Grenoble Hopital Michalon
city: Marseille
country: France
facility: CHU la Conecption
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hopital Saint Louis
city: Pierre-Bénite
country: France
facility: Centre hospitalier Lyon Sud
city: Frankfurt
country: Germany
facility: Klinikum Frankfurt Hoechst
city: Kiel
country: Germany
facility: UniversitatsklinikumUKSH Kiel
city: Marburg
country: Germany
facility: Universitatsklinikum Marburg
city: Stuttgart
country: Germany
facility: Robert-Bosch- Krankenhaus
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Chorzów
country: Poland
facility: Zespół Szpitali Miejskich w Chorzowie
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne Klinika Hematologii i Transplantologii
city: Wrocław
country: Poland
facility: Katedra i Klinika Hematologii
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia (ICO) - Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Palma De Mallorca
country: Spain
facility: Hospital Son ESPASES
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital U. P. La Fe
Study officials:
affiliation: Augusta University
name: Jorge E Cortes, MD
role: PRINCIPAL_INVESTIGATOR
References: