Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613 in Combination With High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥60 Years) With Relapsed/Refractory Acute Myeloid Leukemia (AML)
A Phase III study to evaluate the safety and efficacy of CPI-613 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 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 to high dose cytarabine and mitoxantrone (CHAM) will improve the complete remission (CR) rate in patients 60 years or older with relapsed or refractory AML when compared to HAM alone.
60 Years and up
Accepting Healthy Volunteers?
1. Patient has provided an informed consent prior to initiation of any study specific activities/procedures.
2. Males and females age ≥ 60 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. Failure to respond to one cycle of either standard dose or HiDAC (defined as no decrease in marrow blast percentage from diagnosis on Day 14 marrow), or
3. No response after at least 3 cycles of a hypomethylating agent (azacytidine or decitabine).
4. Relapse is defined as development of recurrent AML (as described by Döhner et al, 2010)6 after CR or CRi has been achieved with a prior chemotherapy or after disease progression on a hypomethylating agent.
5. ECOG PS 0-2.
6. Expected survival >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 use 2 effective contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive, injectable or implantable agent/device or double barrier device (diaphragm + spermicide) 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 (Note: pregnant patients are excluded because the effects of CPI 613 on a fetus are unknown).
8. Fertile men must practice effective contraceptive methods (condom + spermicide) 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 2 weeks prior to treatment with CPI 613. 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), 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).
1. Patients who have received previous cytotoxic chemotherapy treatment for their relapsed or refractory AML. Previous 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 are allowed. Targeted therapies and Hydrea may be taken until the day prior to starting CHAM or HAM therapy.
2. 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.
3. Patients with active Central Nervous System (CNS) involvement (leukemic infiltration, blast in the spinal fluid).
4. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g. active peptic ulcer disease).
5. 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 is unknown). Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at Screening.
6. Female patients of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for 6 months after completion of CHAM or HAM therapy for AML.
7. 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.
8. 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.
9. Patient has known sensitivity to any of the CHAM or HAM medications to be administered during dosing.
10. Life expectancy less than 3 months.
11. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients.
12. Unwilling or unable to follow protocol requirements.
13. Patients with large and recurrent pleural or peritoneal effusions requiring frequent drainage (e.g. weekly).
14. Patients with any amount of clinically significant pericardial effusion that requires drainage.
15. Evidence of ongoing, uncontrolled bacterial, viral or fungal infection.
16. Patients with known human immunodeficiency virus infection.
17. 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.
18. Patients receiving any other standard or investigational treatment for AML, or any other investigational agent for any indication within the past 2 weeks prior to initiation of CPI-613 treatment (the use of Hydrea and/or 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.
19. Patients who have received immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment.
20. Requirement for immediate palliative treatment of any kind including minor surgery.
21. Patients who have received a chemotherapy regimen with autologous stem cell support (bone marrow transplantation) within 6 months of starting CHAM or HAM therapy.
22. Patients who have had allogenic bone marrow transplantation.