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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03504410




Registration number
NCT03504410
Ethics application status
Date submitted
12/04/2018
Date registered
20/04/2018
Date last updated
8/02/2023

Titles & IDs
Public title
Efficacy/Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. in Older Patients With R/R AML
Scientific 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
Secondary ID [1] 0 0
AML003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed/Refractory Acute Myeloid Leukemia 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - CPI-613 + High Dose Cytarabine and Mitoxantrone
Treatment: Drugs - High Dose Cytarabine and Mitoxantrone
Treatment: Drugs - Mitoxantrone, Etoposide and Cytarabine
Treatment: Drugs - Fludarabine, Cytarabine, Filgrastim

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.

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


Treatment: Drugs: 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

Treatment: Drugs: 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

Treatment: Drugs: 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

Treatment: Drugs: 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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Complete Remission (CR)
Timepoint [1] 0 0
12 months

Eligibility
Key inclusion 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
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/11/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
19/01/2022
Sample size
Target
Accrual to date
Final
200
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 0 0
Border Medical Oncology Research Unit - Albury
Recruitment hospital [2] 0 0
Gosford Hospital - Gosford
Recruitment hospital [3] 0 0
Calvary Mater Newcastle Hospital - Waratah
Recruitment hospital [4] 0 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
2250 - Gosford
Recruitment postcode(s) [3] 0 0
2298 - Waratah
Recruitment postcode(s) [4] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Iowa
Country [5] 0 0
United States of America
State/province [5] 0 0
Kentucky
Country [6] 0 0
United States of America
State/province [6] 0 0
New Jersey
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Oregon
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Virginia
Country [13] 0 0
Austria
State/province [13] 0 0
Graz
Country [14] 0 0
Austria
State/province [14] 0 0
Salzburg
Country [15] 0 0
Austria
State/province [15] 0 0
Wien
Country [16] 0 0
Belgium
State/province [16] 0 0
Brugge
Country [17] 0 0
Belgium
State/province [17] 0 0
Brussels
Country [18] 0 0
Belgium
State/province [18] 0 0
Gent
Country [19] 0 0
France
State/province [19] 0 0
Yvelines
Country [20] 0 0
France
State/province [20] 0 0
Amiens
Country [21] 0 0
France
State/province [21] 0 0
Bobigny
Country [22] 0 0
France
State/province [22] 0 0
Caen
Country [23] 0 0
France
State/province [23] 0 0
Grenoble Cedex 9
Country [24] 0 0
France
State/province [24] 0 0
Marseille
Country [25] 0 0
France
State/province [25] 0 0
Nice
Country [26] 0 0
France
State/province [26] 0 0
Paris
Country [27] 0 0
France
State/province [27] 0 0
Pierre-Bénite
Country [28] 0 0
Germany
State/province [28] 0 0
Frankfurt
Country [29] 0 0
Germany
State/province [29] 0 0
Kiel
Country [30] 0 0
Germany
State/province [30] 0 0
Marburg
Country [31] 0 0
Germany
State/province [31] 0 0
Stuttgart
Country [32] 0 0
Korea, Republic of
State/province [32] 0 0
Seoul
Country [33] 0 0
Poland
State/province [33] 0 0
Chorzów
Country [34] 0 0
Poland
State/province [34] 0 0
Gdansk
Country [35] 0 0
Poland
State/province [35] 0 0
Wroclaw
Country [36] 0 0
Spain
State/province [36] 0 0
Badalona
Country [37] 0 0
Spain
State/province [37] 0 0
Barcelona
Country [38] 0 0
Spain
State/province [38] 0 0
Madrid
Country [39] 0 0
Spain
State/province [39] 0 0
Málaga
Country [40] 0 0
Spain
State/province [40] 0 0
Palma De Mallorca
Country [41] 0 0
Spain
State/province [41] 0 0
Salamanca
Country [42] 0 0
Spain
State/province [42] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Cornerstone Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03504410
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jorge E Cortes, MD
Address 0 0
Augusta University
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03504410