E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myelogenous Leukemia (AML) or higher risk Myelodysplastic Syndrome (MDS). |
|
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 |
|
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) |
|
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) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 1 •To evaluate the safety and tolerability of CA-4948 in patients with relapsed / refractory (R/R) acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndrome (hrMDS) • To identify maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D)
Phase 2a: To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT-3) mutations, and patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1 |
|
E.2.2 | Secondary objectives of the trial |
Phase 1 • To characterize the pharmacokinetic (PK) parameters of CA-4948 using noncompartmental analysis and appropriate PK modelling • 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
|
|
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 4. Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization 2016 classification) with the following characteristics.
Phase 1 Dose Escalation . 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 SCT), based on the assessment of the Investigator. OR . Higher-risk R/R MDS (International Prognostic Scoring System-revised score >3.5; Pfeilstocker 2016) that are considered resistant/refractory following at least 2 to 3 cycles of hypomethylating agents, or evidence of early progression
Patients that meet 1 of the following criteria: • R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor • R/R AML with spliceosome mutations of SF3B1 or U2AF1 • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 And • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)
Phase 2a Dose Expansion Patients with: • R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor • R/R AML with spliceosome mutations of SF3B1 or U2AF1 • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 And • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)
5. Acceptable organ function at Screening as described below: a. Estimated creatinine clearance (CrCl) of ≥ 35 mL/min (Appendix H). b. Aspartate aminotransferase or alanine aminotransferase ≤ 2 × ULN c. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome d. White blood cell count ≤ 25,000/μL (hydroxyurea is allowed during Screening and Cycle 1 for cytoreduction, if needed, for patients with AML per Investigator’s discretion. However, hydroxyurea must stop prior to Cycle 2) 6. CPK < Grade 2. 7. For patients on a cholesterol lowering agent that has been associated with CPK elevations, such as statins or fibrates, the agent should be discontinued or replaced with an alternative if medically feasible. Otherwise, it should be reduced to the lowest dose that is biologically effective (ie, the lowest dose required to achieve the desired clinical effect). 8. Ability to swallow and retain oral medications 9. Negative serum pregnancy test in women of childbearing potential (WOCP) 10. WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 180 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 willing to have 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
|
|
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 SCT 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-SCT 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 3 weeks (or 5 half-lives), whichever is shorter, or radiotherapy received 2 weeks prior to the start of CA-4948 Note: Localized radiation or surgical resection of skin cancers is allowed 6. Use of any investigational agent within 3 weeks (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. Patients with active advanced malignant solid tumors. 11. 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 12. Concomitant illnesses that would preclude safe participation in study, identified within approximately 28 days of C1D1, including: a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, 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 study participation or CA-4948 administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of the study results and, in the Investigator's opinion, would make the patient inappropriate for entry into this study 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) 13. Pregnant or lactating 14. History of ≥ Grade 3 rhabdomyolysis without complete recovery |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1 • Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations
Phase 2a Clinical response in AML or hrMDS assessed as follows: • AML: Proportion of patients who achieve CR + CRh • hrMDS: ORR (CR + PR)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Phase 1 • PK parameters of CA-4948 measured by maximum plasma concentration (Cmax), trough plasma concentration (Cmin), time to Cmax (Tmax,) area under the concentration-time curve from 0-24 hours (AUC 0-24), area under the concentration-time curve from 0 to infinity (AUC 0-inf), and half-life (T ½)
Clinical response in AML or hrMDS assessed as follows: • AML: o Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh) o Proportion of patients who achieve complete response with incomplete hematological recovery (CRi), or CR, or CRh, or partial response (PR), or morphologic leukemia-free state (MLFS) o Duration of response (DOR) o Time to response • hrMDS: o Overall response rate (ORR): proportion of patients who achieve CR or PR o DOR o Time to response • Transfusion independence in AML or hrMDS
Phase 2 • 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, with or without hematological improvement • DOR • Time to responses • Transfusion independence •Overall survival (OS)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 |
|
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 | 2 |
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 |
|
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
|
The end of the study is defined as after the last patient has completed the SFU visit and there are no longer any patients will being followed. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial months | 60 |