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

• Sponsor: Cornerstone Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03504410
• Collaborator: (none)
• Enrollment: 194
• Locations: 60
• Arms: 2
• Actual Duration (Months): 33
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory Acute Myeloid Leukemia	Drug: CPI-613 + High Dose Cytarabine and Mitoxantrone; Drug: High Dose Cytarabine and Mitoxantrone; Drug: Mitoxantrone, Etoposide and Cytarabine; Drug: Fludarabine, Cytarabine, Filgrastim	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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) Therapy and Control Sub-groups: Combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and Combination of Fludarabine, Cytarabine, and Filgrastim (FLAG) in Older Patients (≥ 50 Years) With Relapsed/Refractory Acute Myeloid Leukemia (AML)
• Actual Study Start Date: Nov 12, 2018
• Actual Primary Completion Date: Aug 13, 2021
• Actual Study Completion Date: Aug 13, 2021

Arms and Interventions

Arm	Intervention/Treatment
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.	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 Names: CPI-613, CHAM
Active Comparator: Control (HAM) and control sub-groups (MEC and FLAG) 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; 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 Names: HAM ; Drug: Mitoxantrone, Etoposide and 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; Other Names: MEC ; Drug: Fludarabine, Cytarabine, Filgrastim; 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; Other Names: FLAG

Outcome Measures

Primary Outcome Measures

1. Complete Remission (CR) [8 months]

   Complete disappearance of all clinical evidence of disease

Secondary Outcome Measures

1. Overall Survival (OS) [12 months]

   the duration from the date of randomization to the date of death from any cause

2. CR+CRh [12 months]

   Complete Remission + CR with partial hematological recovery (CRh)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

4. 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

5. Persistent disease after at least 2 cycles of a hypomethylating agent (azacytidine or decitabine) with or without venetoclax

6. 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

7. ECOG PS 0-2

8. Expected survival greater than 3 months

9. 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)

10. 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

11. Good state of mental health, ability to understand and willingness to sign the informed consent form (ICF)

12. 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

13. 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)

1. 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%

2. No marked baseline prolongation of QT/QTc interval (repeated exhibition of a QTc interval > 480 ms for both male and female patients)

3. No history of additional risk factors for torsade de pointes (e.g. clinically significant heart failure, hypokalemia, immediate family history of Long QT Syndrome)

4. 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):

19. 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

20. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of recurrent or residual disease

21. Adequately treated cervical carcinoma in situ without evidence of disease

22. Prostate cancer Stage 1

23. 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))

24. Patients who have received immunotherapy of any type within the past 1 week prior to initiation of CPI-613® (devimistat) treatment

25. Requirement for immediate palliative treatment of any kind including minor surgery

26. 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)

27. 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.)

28. 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

1. 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

1. Strong CYP450 inducers should be prohibited

2. Etoposide contraindications

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

1. Fludarabine contraindications

•. Contraindicated in those patients who are hypersensitive to this drug or its components

1. Filgrastim contraindications •. Contraindicated in patients with known hypersensitivity to E coli-derived proteins, Filgrastim, or any component of the product

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Honor Health Research Institute	Scottsdale	Arizona	United States	85258
2	Chao Family Comprehensive Cancer Center (University of California Irvine)	Orange	California	United States	92868
3	California Pacific Medical Center	San Francisco	California	United States	94115
4	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
5	University of Chicago	Chicago	Illinois	United States	60637
6	Loyola University Medical Center	Maywood	Illinois	United States	60153
7	University of Iowa-Holden Cancer Care Center	Iowa City	Iowa	United States	52242
8	University of Kentucky	Lexington	Kentucky	United States	40436
9	Norton Cancer Institute	Louisville	Kentucky	United States	40207
10	Atlantic Health System	Morristown	New Jersey	United States	07960
11	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
12	Stony Brook University Hospital	Long Island City	New York	United States	11794
13	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
14	UNC Chapel Hill	Chapel Hill	North Carolina	United States	27599
15	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
16	University of Cincinnati	Cincinnati	Ohio	United States	45219
17	Cleveland Clinic	Cleveland	Ohio	United States	44195
18	Oregon Health & Science University	Portland	Oregon	United States	97239
19	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
20	University of Texas - Southwestern Medical Center	Dallas	Texas	United States	75390
21	MD Andrson Cancer Center	Houston	Texas	United States	77030
22	Baylor Temple (BSW)	Temple	Texas	United States	76508
23	University of Virginia	Charlottesville	Virginia	United States	22908
24	Border Medical Oncology Research Unit	Albury	New South Wales	Australia	2640
25	Gosford Hospital	Gosford	New South Wales	Australia	2250
26	Calvary Mater Newcastle Hospital	Waratah	New South Wales	Australia	2298
27	Royal Perth Hospital	Perth	Western Australia	Australia	6000
28	Universitätsklinik für Innere Medizin	Graz		Austria	8036
29	Paracelsus Medical University	Salzburg		Austria	5020
30	Hanuschkrankenhaus der WGKK	Wien		Austria	1140
31	Algemeen Ziekenhuis Sint-Jan	Brugge		Belgium	8000
32	Clinique Universitaire St Luc	Brussels		Belgium	1200
33	UN Gent	Gent		Belgium	9000
34	Centre Hospitalier de Versailles - Hôpital André Mignot	Le Chesnay	Yvelines	France	78157
35	CHU Amiens	Amiens		France	80054
36	Service d'Hématologie Clinique, Hôpital Avicenne-APHP-Université Paris	Bobigny		France	9300
37	CHU de Caen	Caen		France	14033
38	Centre Hospitalier Universitaire Grenoble Hopital Michalon	Grenoble Cedex 9		France	38043
39	CHU la Conecption	Marseille		France	13005
40	CHU de Nice	Nice		France	06202
41	Hopital Saint Louis	Paris		France	75010
42	Centre hospitalier Lyon Sud	Pierre-Bénite		France	69495
43	Klinikum Frankfurt Hoechst	Frankfurt		Germany	65929
44	UniversitatsklinikumUKSH Kiel	Kiel		Germany	24105
45	Universitatsklinikum Marburg	Marburg		Germany	35033
46	Robert-Bosch- Krankenhaus	Stuttgart		Germany	70376
47	Seoul National University Hospital	Seoul		Korea, Republic of	03080
48	Severance Hospital	Seoul		Korea, Republic of	03722
49	Asan Medical Center	Seoul		Korea, Republic of	05505
50	Samsung Medical Center	Seoul		Korea, Republic of	06351
51	Zespół Szpitali Miejskich w Chorzowie	Chorzów		Poland	41500
52	Uniwersyteckie Centrum Kliniczne Klinika Hematologii i Transplantologii	Gdańsk		Poland	80211
53	Katedra i Klinika Hematologii	Wrocław		Poland	50556
54	Institut Catala d'Oncologia (ICO) - Hospital Universitari Germans Trias i Pujol	Badalona		Spain	08916
55	Hospital Vall d'Hebron	Barcelona		Spain	08035
56	MD Anderson Cancer Center	Madrid		Spain	28033
57	Hospital Universitario Virgen de la Victoria	Málaga		Spain	29010
58	Hospital Son ESPASES	Palma De Mallorca		Spain	07120
59	Hospital Clínico Universitario de Salamanca	Salamanca		Spain	37007
60	Hospital U. P. La Fe	Valencia		Spain	46026

Sponsors and Collaborators

• Cornerstone Pharmaceuticals

Investigators

• Principal Investigator: Jorge Eduardo Cortes, MD, Augusta University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cornerstone Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03504410
• Other Study ID Numbers: AML003
• First Posted: Apr 20, 2018
• Last Update Posted: Jul 27, 2022
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Fludarabine; Etoposide; Mitoxantrone

Study Results

No Results Posted as of Jul 27, 2022