Efficacy/Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. in Older Patients With R/R AML

NCT03504410 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: AML003
• Study Type: interventional
• Target: 200
• Locations: 8 countries
• Sites: 57

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.

Conditions

Relapsed/Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Complete Remission (CR)

  Complete disappearance of all clinical evidence of disease

  12 months

Study Arms (2)

CPI-613 + HD Cytarabine and Mitoxantrone

EXPERIMENTAL

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.

Drug: CPI-613 + High Dose Cytarabine and Mitoxantrone

Control (HAM) and control sub-groups (MEC and FLAG)

ACTIVE COMPARATOR

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. Mitoxantrone, Etoposide and Cytarabine Etoposide 80mg/m over 60 minutes as a central line IV infusion; 6 doses Day 1 though 6 Cytarabine 1000mg/m2 over 3 hours as a central line IV infusion: 6 doses, Day 1 through 6 Mitoxantrone 6 mg/m2 over 30 minutes as a central line IV infusion: 6 dose, Day 1 through 6 Fludarabine, Cytarabine and Filgrastim Fludarabine 30mg/m2/day over 30 minutes as a central line IV infusion; 5 doses Day 1 though 5 Cytarabine 2g/m2 over 4 hours as a central line IV infusion: 4 hours after Fludarabine: 5 doses, Day 1 through 5 Filgrastim 5µg/kg/day by SQ or as per institutional guidelines starting from Day 1 through Day 5

Drug: High Dose Cytarabine and Mitoxantrone; Drug: Mitoxantrone, Etoposide and Cytarabine; Drug: Fludarabine, Cytarabine, Filgrastim

Interventions

CPI-613 + High Dose Cytarabine and Mitoxantrone DRUG

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

Also known as: CPI-613, CHAM

CPI-613 + HD Cytarabine and Mitoxantrone

High Dose Cytarabine and Mitoxantrone DRUG

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

Also known as: HAM

Control (HAM) and control sub-groups (MEC and FLAG)

Mitoxantrone, Etoposide and Cytarabine DRUG

Mitoxantrone, Etoposide and Cytarabine Etoposide 80mg/m over 60 minutes as a central line IV infusion; 6 doses Day 1 though 6 Cytarabine 1000mg/m2 over 3 hours as a central line IV infusion: 6 doses, Day 1 through 6 Mitoxantrone 6 mg/m2 over 30 minutes as a central line IV infusion: 6 dose, Day 1 through 6

Also known as: MEC

Control (HAM) and control sub-groups (MEC and FLAG)

Fludarabine, Cytarabine, Filgrastim DRUG

Fludarabine, Cytarabine and Filgrastim Fludarabine 30mg/m2/day over 30 minutes as a central line IV infusion; 5 doses Day 1 though 5 Cytarabine 2g/m2 over 4 hours as a central line IV infusion: 4 hours after Fludarabine: 5 doses, Day 1 through 5 Filgrastim 5µg/kg/day by SQ or as per institutional guidelines starting from Day 1 through Day 5

Also known as: FLAG

Control (HAM) and control sub-groups (MEC and FLAG)

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has provided an informed consent prior to initiation of any study specific activities/procedures
• Males and females age ≥ 50 years must have histologically documented AML that is relapsed from, or refractory to, prior standard therapies
• Refractory is defined as failure to achieve CR or CRi following:
• 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
• Persistent disease after at least 2 cycles of a hypomethylating agent (azacytidine or decitabine) with or without venetoclax
• 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
• ECOG PS 0-2
• Expected survival greater than 3 months
• 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)
• 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
• Good state of mental health, ability to understand and willingness to sign the informed consent form (ICF)
• 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
• 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)

You may not qualify if:

• 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)
• Vulnerable adult and patient whose health conditions does not allow them to give their consent
• 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
• Patients with active Central Nervous System (CNS) involvement (leukemic infiltration, blast in the spinal fluid)
• Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g. active peptic ulcer disease)
• 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
• 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
• 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
• 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
• Known hypersensitivity to study treatment drugs or any of the excipient(s) contained in the drug formulation
• Life expectancy less than 3 months
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
• Unwilling or unable to follow protocol requirements
• Patients with large and recurrent pleural or peritoneal effusions requiring frequent drainage (e.g. weekly)
• Patients with any amount of clinically significant pericardial effusion that requires drainage.

Sponsors & Collaborators

• Cornerstone Pharmaceuticals: lead

Study Sites (60)

Honor Health Research Institute

Scottsdale, Arizona, 85258, United States

Location

Chao Family Comprehensive Cancer Center (University of California Irvine)

Orange, California, 92868, United States

Location

California Pacific Medical Center

San Francisco, California, 94115, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Loyola University Medical Center

Maywood, Illinois, 60153, United States

Location

University of Iowa-Holden Cancer Care Center

Iowa City, Iowa, 52242, United States

Location

University of Kentucky

Lexington, Kentucky, 40436, United States

Location

Norton Cancer Institute

Louisville, Kentucky, 40207, United States

Location

Atlantic Health System

Morristown, New Jersey, 07960, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08901, United States

Location

Stony Brook University Hospital

Long Island City, New York, 11794, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

UNC Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Wake Forest Baptist Health

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45219, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

University of Texas - Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MD Andrson Cancer Center

Houston, Texas, 77030, United States

Location

Baylor Temple (BSW)

Temple, Texas, 76508, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Border Medical Oncology Research Unit

Albury, New South Wales, 2640, Australia

Location

Gosford Hospital

Gosford, New South Wales, 2250, Australia

Location

Calvary Mater Newcastle Hospital

Waratah, New South Wales, 2298, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Universitätsklinik für Innere Medizin

Graz, 8036, Austria

Location

Paracelsus Medical University

Salzburg, 5020, Austria

Location

Hanuschkrankenhaus der WGKK

Vienna, 1140, Austria

Location

Algemeen Ziekenhuis Sint-Jan

Bruges, 8000, Belgium

Location

Clinique Universitaire St Luc

Brussels, 1200, Belgium

Location

UN Gent

Ghent, 9000, Belgium

Location

Centre Hospitalier de Versailles - Hôpital André Mignot

Le Chesnay, Yvelines, 78157, France

Location

CHU Amiens

Amiens, 80054, France

Location

Service d'Hématologie Clinique, Hôpital Avicenne-APHP-Université Paris

Bobigny, 9300, France

Location

CHU de Caen

Caen, 14033, France

Location

Centre Hospitalier Universitaire Grenoble Hopital Michalon

Grenoble, 38043, France

Location

CHU la Conecption

Marseille, 13005, France

Location

CHU de Nice

Nice, 06202, France

Location

Hopital Saint Louis

Paris, 75010, France

Location

Centre hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

Klinikum Frankfurt Hoechst

Frankfurt, 65929, Germany

Location

UniversitatsklinikumUKSH Kiel

Kiel, 24105, Germany

Location

Universitatsklinikum Marburg

Marburg, 35033, Germany

Location

Robert-Bosch- Krankenhaus

Stuttgart, 70376, Germany

Location

Zespół Szpitali Miejskich w Chorzowie

Chorzów, 41500, Poland

Location

Uniwersyteckie Centrum Kliniczne Klinika Hematologii i Transplantologii

Gdansk, 80211, Poland

Location

Katedra i Klinika Hematologii

Wroclaw, 50556, Poland

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Institut Catala d'Oncologia (ICO) - Hospital Universitari Germans Trias i Pujol

Badalona, 08916, Spain

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

MD Anderson Cancer Center

Madrid, 28033, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Son ESPASES

Palma de Mallorca, 07120, Spain

Location

Hospital Clínico Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital U. P. La Fe

Valencia, 46026, Spain

Location

Related Publications (1)

• Pardee TS, Powell BL, Larson RA, Maly J, Keng M, Foster M, Choi EJ, Sill H, Cluzeau T, Jeyakumar D, Frankfurt O, Patel P, Schuster M, Koller E, Costello R, Platzbecker U, Montesinos P, Vives S, Nazha A, Cook R, Vigil-Gonzales C, Chantepie S, Luther S, Cortes J. Devimistat plus chemotherapy vs chemotherapy alone for older relapsed or refractory patients with AML: results of the ARMADA trial. Blood Neoplasia. 2024 Mar 29;1(2):100009. doi: 10.1016/j.bneo.2024.100009. eCollection 2024 Jun.

  PMID: 40454396 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

devimistat; Cytarabine; Mitoxantrone; Etoposide; fludarabine; Filgrastim

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Glycosides; Carbohydrates; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Sanejev Luther
• Organization: Cornerstone Pharmaceuticals Inc

sanjeev.luther@cornerstonepharma.com

585-978-1351

Study Officials

• Jorge E Cortes, MD

  Augusta University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2018
• First Posted: April 20, 2018
• Study Start: November 12, 2018
• Primary Completion: October 25, 2021
• Study Completion: January 19, 2022
• Last Updated: February 8, 2023
• Results First Posted: December 13, 2022

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

BE (3); DE (4); AU (4); PL (3); KR (4); FR (9); ES (7); US (23)