E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS). |
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E.1.1.1 | Medical condition in easily understood language |
AML: cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made MDS: group of disorders caused by poorly formed blood cells or ones that don't work properly |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001941 |
E.1.2 | Term | AML |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068361 |
E.1.2 | Term | MDS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 1 • To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for CA-4948 in monotherapy in patients with Acute Myelogenous Leukemia (AML) or intermediate, high, or very high risk Myelodysplastic Syndrome (hrMDS) based on the safety and tolerability, dose-limiting toxicities (DLTs), and pharmacokinetic (PK) and pharmacodynamic findings.
Phase 1b • To determine MTD and RP2D for CA 4948 in combination with azacitidine (AZA) in treatment naïve patients with AML or hrMDS or in combination with venetoclax (VEN) in relapsed/ refractory (R/R) patients with AML or hrMDS after first line treatment based on the safety and tolerability, DLTs and PK and pharmacodynamic findings
Phase 2a: To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R FLT-3 AML, and patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1 |
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E.2.2 | Secondary objectives of the trial |
Phase 1 and Phase 1b - To characterize the PK parameters of CA 4948 using non-compartmental analysis and appropriate PK model - To assess anti-cancer activity
Phase 2a: - To assess tolerability and long-term safety - To further assess anti-cancer activity of CA-4948 at RP2D
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females >= 18 years of age 2. Life expectancy of at least 3 months 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 (Appendix A) 4. Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization [WHO] 2016 classification) with the following characteristics.
Phase 1 Dose Escalation (Monotherapy) . AML (primary or secondary, including treatment-related; European Leukemia Net category) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation), based on the assessment of the Investigator. OR . High-risk R/R MDS (IPSS-R criteria) that are considered resistant/refractory following at least 2 to 3 cycles naïve of HMA or evidence of early progression
Phase 1b (Combination Therapy) Doublet Arm: CA-4948 + AZA Patients with: • IPSS- R High, hrMDS • Ineligible for intensive chemotherapy Doublet Arm: CA-4948 + VEN Patients with: • R/R AML or hrMDS, after first line therapy
Phase 2a Dose Expansion (Monotherapy) Patients with: · R/R AML with FLT3 mutations, R/R including a FLT3 inhibitor · R/R AML with spliceosome mutations of SF3B1 or U2AF1 · R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1; bone marrow blast count ≥8%: ineligible for intensive chemotherapy · Number of pretreatments: 1 or 2 5. Acceptable organ function at Screening as described below: a. Estimated creatinine clearance (CrCl) of ≥ 35 mL/min (Appendix H). b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2 × ULN c. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome d. WBC ≤ 25,000/µL (Hydroxyurea is allowed at pre-treatment and at least up to the first cycle for cytoreduction if needed for patients with AML) 6. Creatinine phosphokinase (CPK) < Grade 2. 7. Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start 8. Ability to swallow and retain oral medications 9. Negative serum pregnancy test in women of childbearing potential 10. Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of CA-4948 11. Willing and able to provide written informed consent and comply with the requirements of the trial 12. Biopsy requirement for AML and MDS: patients must be amenable to serial bone marrow sampling and peripheral blood sampling during the study. The diagnosis and evaluation of AML and MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis is made from the core biopsy
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E.4 | Principal exclusion criteria |
1. Diagnosed with acute promyelocytic leukemia (APL, M3) 2. Known active central nervous system (CNS) leukemia; patients with previously treated CNS disease may participate if asymptomatic as determined by treating physician (without symptomatic active disease for at least 4 weeks prior to the first dose of treatment, and any neurologic symptoms have returned to baseline) 3. Allogeneic hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948 Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval 4. Chronic myelogenous leukemia 5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of CA-4948. Localized radiation or surgical resection of skin cancers is allowed 6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter, prior to start of CA-4948 7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of CA 4948 unless approved by the Medical Monitor 8. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study 9. Major surgery, other than diagnostic surgery, <28 days from the start of CA-4948; minor surgery <14 days from the start of CA-4948 Note: Insertion of a vascular access device is not considered minor surgery 10. Known hypersensitivity to AZA or mannitol, as stated per label, Appendix J (Phase 1b only) 11. Patients with active advanced malignant solid tumors. 12. Viral Infections: a. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness. If HIV virus is undetectable and maintained on treatment, enrolment may be allowed after discussion with the Sponsor. b. Hepatitis B virus (HBV) DNA positive or hepatitis C virus (HCV) infection < 6 months prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis Note: testing only required in patients with history of HBV or history of HCV < 6 months prior to start of CA-4948 13. Concomitant illnesses that would preclude safe participation in study, including: a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, or QTc with Fridericia’s correction (QTcF) that is unmeasurable or > 450 msec on screening electrocardiogram (ECG) Note: for QTcF > 450 sec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the three screening ECGs must be ≤ 450 msec in order to meet eligibility for trial participation b. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948. This includes major abdominal surgery and/or significant bowel resection and/or gastrointestinal diseases that could alter the assessment of PK or safety c. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or CA-4948 administration, may interfere with the informed consent process and/or with compliance with the requirements of the trial, or may interfere with the interpretation of the trial results and, in the Investigator's opinion, would make the patient inappropriate for entry into this trial d. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) 14. Pregnant or lactating
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1 Monotherapy/Phase 1b (Combination Therapy) • MTD (defined as the highest dose at which there is < 33% DLT rate in the first cycle of treatment in a minimum of 6 patients [time frame: 28 days]) • RP2D (determined by the Sponsor in consultation with the Clinical Safety Committee [CSC], considering all aspects of safety, tolerability, biologic activity, PK and preliminary efficacy in the trial population [time frame: 24 months]) • Safety measured by adverse events (AEs), electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations
Phase 2a (Monotherapy Expansion) .Clinical response in AML or hrMDS assessed as follows: • AML: Proportion of patients who achieve CR + CRh • hrMDS: ORR of CR + PR + mCR
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Phase 1 Monotherapy/Phase 1b (Combination Therapy) • PK parameters of CA 4948 measured by Cmax, Cmin, Tmax, AUC 0-24, AUC 0-inf, and T ½ (time frame 24 months) Clinical response in AML or hrMDS assessed as follows: • AML: o Proportion of patients who reach CR + CRh o Proportion of patients who reach CRi, or CR or CRh • hrMDS: ORR of CR + PR + mCR • Transfusion independence
Phase 2a (Monotherapy Expansion) • Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations Clinical response in AML or hrMDS assessed as follows: • Proportion of patients with AML who achieve CR or CRh or CRi • Proportion of patients with hrMDS who achieve CR or PR or mCR • DOR • Time to response • Transfusion independence • OS
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Part 1b emavusertib + venetoclax doublet is not open to further enrollment. |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Israel |
United States |
Czechia |
France |
Germany |
Italy |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 48 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 48 |