PALOMA: Comparison of Therapies Before Stem Cell Transplantation in Patients With Higher Risk MDS and Oligoblastic AML

Sponsor

GWT-TUD GmbH (Other)

Overall Status

Recruiting

CT.gov ID

NCT04061239

Collaborator

(none)

150

Enrollment

Locations

Arms

61.4

Anticipated Duration (Months)

5.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
MDS AML	Drug: CPX-351 Drug: Daunorubicin Drug: Cytarabine Drug: Azacitidine	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 19, 2019

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CPX-351 Arm CPX-351 is a liposomal formulation with a fixed 5:1 molar ratio of cytarabine and daunorubicin. It will be administered as a 90-minute intravenous infusion. The treatment includes up to 2 cycles of induction as follows: 1 x CPX-351 1st induction: daunorubicin 44 mg/m² and cytarabine 100 mg/m² in liposomes on days 1, 3, and 5 1 x CPX-351 2nd induction: daunorubicin 44 mg/m² and cytarabine 100 mg/m² in liposomes on days 1 and 3 Each induction cycle will last 28 days. Depending on the type and extent of response as well as toxicity, the patient may continue on to consolidation therapy after induction or be discontinued from the treatment phase and transferred directly to alloHCT, if applicable. CPX-351 consolidation is with daunorubicin 29 mg/m² and cytarabine 65 mg/m² in liposomes on days 1 and 3. For patients < 60 years up to 3 consolidation cycles and for patients ≥ 60 years up to 2 consolidation cycles are allowed.	Drug: CPX-351 CPX-351 is a liposomal formulation with a fixed 5:1 molar ratio of cytarabine and daunorubicin. It will be administered as a 90-minute intravenous infusion. Other Names: Vyxeos
Other: CCR Arm The conventional care regimens (CCR) arm has 2 options according to the discretion of the investigator: conventional "7+3" cytarabine/daunorubicin chemotherapy regimen treatment with s.c. Azacitidine	Drug: Daunorubicin Daunorubicin is commercially available as a powder for reconstitution in 20 mg vials. In this trial, daunorubicin should be administered as an IV infusion over 60 min. Drug: Cytarabine Cytarabine is commercially available as vials/bottles for preparation of diluted infusion solution. Cytarabine will be administrated intravenously. In this trial, cytarabine is administered as a continuous infusion. Drug: Azacitidine Azacitidine at 75mg/m² for 7 days. Patients should receive a minimum of 2 and up to 6 cycles. Other Names: Vidaza

Arm

Intervention/Treatment

Experimental: CPX-351 Arm

CPX-351 is a liposomal formulation with a fixed 5:1 molar ratio of cytarabine and daunorubicin. It will be administered as a 90-minute intravenous infusion. The treatment includes up to 2 cycles of induction as follows: 1 x CPX-351 1st induction: daunorubicin 44 mg/m² and cytarabine 100 mg/m² in liposomes on days 1, 3, and 5 1 x CPX-351 2nd induction: daunorubicin 44 mg/m² and cytarabine 100 mg/m² in liposomes on days 1 and 3 Each induction cycle will last 28 days. Depending on the type and extent of response as well as toxicity, the patient may continue on to consolidation therapy after induction or be discontinued from the treatment phase and transferred directly to alloHCT, if applicable. CPX-351 consolidation is with daunorubicin 29 mg/m² and cytarabine 65 mg/m² in liposomes on days 1 and 3. For patients < 60 years up to 3 consolidation cycles and for patients ≥ 60 years up to 2 consolidation cycles are allowed.

Drug: CPX-351

CPX-351 is a liposomal formulation with a fixed 5:1 molar ratio of cytarabine and daunorubicin. It will be administered as a 90-minute intravenous infusion.

Other Names:

Vyxeos

Other: CCR Arm

The conventional care regimens (CCR) arm has 2 options according to the discretion of the investigator: conventional "7+3" cytarabine/daunorubicin chemotherapy regimen treatment with s.c. Azacitidine

Drug: Daunorubicin

Daunorubicin is commercially available as a powder for reconstitution in 20 mg vials. In this trial, daunorubicin should be administered as an IV infusion over 60 min.

Drug: Cytarabine

Cytarabine is commercially available as vials/bottles for preparation of diluted infusion solution. Cytarabine will be administrated intravenously. In this trial, cytarabine is administered as a continuous infusion.

Drug: Azacitidine

Azacitidine at 75mg/m² for 7 days. Patients should receive a minimum of 2 and up to 6 cycles.

Other Names:

Vidaza

Outcome Measures

Primary Outcome Measures

2-year EFS in both arms [2 years]
To compare the event-free survival (EFS) at 2 years of CPX-351 vs. CCR before allogeneic blood cell transplantation (alloHCT) as first line treatment in patients with higher risk MDS and oligoblastic AML.

Secondary Outcome Measures

Response rate [2 years]
To compare best and overall response rate of CPX-351 vs. CCR according to AML-ELN and MDS-IWG criteria
Toxicity Assessment [2 years]
To compare the safety and tolerability of CPX-351 vs. CCR measured by NCI CTCAE v5.0
Proportion of patients proceeding to alloHCT [2 years]
To compare the effects of CPX-351 vs. CCR on the proportion of patients proceeding to alloHCT
Minimal residual disease [2 years]
To compare the effect of CPX-351 vs. CCR on minimal residual disease which will be assessed at all times of bone marrow puncture
Patient's quality of life [2 years]
To compare the effect of CPX-351 vs. CCR on the quality of life. It will be measured using the EORTC-QLQ30 questionnaire

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Ordensklinikum Linz Elisabethinen GmbH	Linz	Austria	4020
2	Uniklinikum Salzburg - Landeskrankenhaus	Salzburg	Austria	5020
3	Universitätsklinikum Aachen	Aachen	Germany	52074
4	Universitätsklinikum Augsburg	Augsburg	Germany	86156
5	Helios Klinikum Berlin-Buch GmbH	Berlin	Germany	13125
6	Universitätsklinikum Bonn (UKB)	Bonn	Germany	53127
7	Klinikum Chemnitz-gGmbH	Chemnitz	Germany	09113
8	Universitätsklinikum Carl Gustav Carus Dresden	Dresden	Germany	01307
9	Universitätsklinikum Düsseldorf	Düsseldorf	Germany	40225
10	Universitätsklinikum Essen	Essen	Germany	45122
11	Klinikum Frankfurt (Oder) GmbH	Frankfurt	Germany	15236
12	Universitätsklinikum Frankfurt	Frankfurt	Germany	60590
13	Universitätsklinikum Halle	Halle	Germany	06120
14	Medizinische Hochschule Hannover	Hannover	Germany	30625
15	Universitätsklinikum Heidelberg	Heidelberg	Germany	69120
16	Universitätsklinikum Jena	Jena	Germany	07740
17	Gemeinschaftsklinikum Mittelrhein gGmbH	Koblenz	Germany	56068
18	Universitätsklinikum Köln	Köln	Germany	50937
19	Universitätsklinikum Leipzig AöR	Leipzig	Germany
20	Universitätsmedizin Mannheim	Mannheim	Germany	68167
21	Klinikum rechts der Isar der TU München	München	Germany	81675
22	Universitätsklinikum Münster	Münster	Germany	48149
23	Klinikum Nürnberg	Nürnberg	Germany	90419
24	Universitätsmedizin Rostock	Rostock	Germany	18055
25	Robert-Bosch-Krankenhaus Stuttgart	Stuttgart	Germany	70376
26	Universitätsklinikum Tübingen	Tübingen	Germany	72076
27	Universitätsklinikum Ulm	Ulm	Germany	89081

Sponsors and Collaborators

GWT-TUD GmbH

Investigators

Principal Investigator: Uwe Platzbecker, Prof., Universitätsklinikum Leipzig AöR

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

GWT-TUD GmbH

ClinicalTrials.gov Identifier:

NCT04061239

Other Study ID Numbers:

PALOMA

First Posted:

Aug 19, 2019

Last Update Posted:

Aug 19, 2021

Last Verified:

Aug 1, 2021

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Cytarabine

Azacitidine

Daunorubicin

Study Results

No Results Posted as of Aug 19, 2021