Clinical trial NCT04061239: Comparison of Therapies Before Stem Cell Transplantation in Patients With Higher Risk MDS and Oligoblastic AML
Official title: Primary Comparison of Liposomal Anthracycline Based Treatment Versus Conventional Care Strategies Before Allogeneic Stem Cell Transplantation in Patients With Higher Risk MDS and Oligoblastic AML
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: MDS
AML
Lead sponsor: GWT-TUD GmbH
Sponsor class: OTHER
First posted: 2019-08-19
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To compare the event-free survival at 2 years of CPX-351 vs. conventional care regimens before allogeneic blood cell transplantation as first line treatment in patients with higher risk MDS and oligoblastic AML.

Detailed description: Allogeneic stem cell transplantation (alloHCT) is considered the only potentially curative treatment option for MDS patients and is therefore often considered the standard treatment for mainly higher-risk MDS patients up to the age of 75 years. One common approach to "bridge" higher-risk MDS from the time of diagnosis to transplantation is a treatment with hypomethylating agents such as azacitidine due to its anticipated low toxicity profile. Alternative strategies are intensive 7+3 chemotherapy with anthracycline and cytarabine or direct and immediate transplantation. By this strategy the time interval for donor search can be significantly prolonged leading to a higher proportion of success.Nevertheless, not every patient initially eligible for transplantation undergoes this procedure subsequently. A direct prospective comparison of different therapeutic approaches as outlined above versus CPX-351 prior to alloHCT has not been performed so far and is subject of the PALOMA trial. We hypothesize that CPX-351 will lead to higher and more durable response rates including a more favourable safety profile and long-term outcome compared to currently used conventional care regimens approaches prior to alloHCT.

Eligibility criteria: Inclusion Criteria:

* Male and female adult patients, 18-75 years of age
* Diagnosis of high risk MDS including oligoblastic non-proliferative (WBC \<13 Gpt/l) AML up to 29% of bone marrow blasts
* Availability of BM blast count from central morphology
* Bone marrow blasts ≥ 5%
* IPSS score intermediate or high
* alloHCT intended within the next 6 months
* ECOG performance status of 0 or 1
* Signed informed consent
* Laboratory values fulfilling the following:
* Serum creatinine \< 2.0 mg/dL
* Serum total bilirubin \< 2.0 mg/dL
* Serum alanine aminotransferase or aspartate aminotransferase \< 3 times the ULN
* Cardiac ejection fraction (LVEF) ≥ 50% by echocardiography
* Contraception:
* Female subjects of childbearing potential† must agree to use a medically acceptable method of contraception for at least 2 months prior to the first dose of CPX-351 and consent of female patients to use a medically acceptable method of contraception throughout the entire study period and for 6 months following the last dose of CPX-351. Medically acceptable methods of contraception that may be used by the patient include abstinence, diaphragm and spermicide, intrauterine device (IUD), condom and vaginal spermicide, hormonal contraceptives (patients must be stable on hormonal contraceptives for at least the prior 3 months), surgical sterilization, or post-menopausal (≥2 years of amenorrhea). Medically acceptable methods of contraception that may be used by the male partner of a female patient are condom and spermicide or vasectomy (\>6 months prior to Day-1) and are to be used throughout the entire study period and for 6 months following the last dose of CPX-351.
* Male patients must be willing to refrain from sperm donation for 6 months following the last dose of CPX-351 and must use adequate contraception throughout the entire study period and for 6 months following the last dose of CPX-351.
* Combined oral contraceptive pills are not recommended. It is recommended that during the study two medically accepted methods of contraception (e.g. as hormonal contraceptive methods along with a condom) apply.

Exclusion Criteria:

* Patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or
* polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible.
* WHO-2016 defined AML entities: AML with t(15;17), PML-RARA; AML with t(8;21), RUNX1-RUNX1T1, AML with inv(16)/t(16;16), CBFβ-MYH11; AML with biallelic CEBPA mutation; AML with mutated FLT3 or NPM1.
* Clinical evidence of active CNS leukemia.
* Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
* Any major surgery or radiation therapy within four weeks prior screening.
* Patients with prior treatment of either CPX-351, hypomethylating agents, cytarabine or intensive chemotherapy for high-risk MDS or AML.
* Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
* Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent.
* Patients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (NYHA Class III or IV staging).
* Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs.
* Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values).
* Hypersensitivity to cytarabine, daunorubicin or liposomal products.
* History of Wilson's disease or other copper-metabolism disorder.
* Female patients who are pregnant or lactating.

Primary outcomes:
measure: 2-year EFS in both arms
timeFrame: 2 years
Secondary outcomes:
measure: Response rate
timeFrame: 2 years
measure: Toxicity Assessment
timeFrame: 2 years
measure: Proportion of patients proceeding to alloHCT
timeFrame: 2 years
measure: Minimal residual disease
timeFrame: 2 years
measure: Patient's quality of life
timeFrame: 2 years
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen GmbH
city: Salzburg
country: Austria
facility: Uniklinikum Salzburg - Landeskrankenhaus
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch GmbH
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn (UKB)
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz-gGmbH
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum Frankfurt (Oder) GmbH
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein gGmbH
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus Stuttgart
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
Study officials:
affiliation: Universitätsklinikum Leipzig AöR
name: Uwe Platzbecker, Prof.
role: PRINCIPAL_INVESTIGATOR
References: