DasaHIT: Dasatinib Holiday for Improved Tolerability

• Sponsor: University of Jena (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02890784
• Collaborator: (none)
• Enrollment: 291
• Locations: 53
• Arms: 2
• Anticipated Duration (Months): 78.9
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Treatment optimization for patients with chronic myeloid leukemia (CML) with treatment naïve disease (1st line) and patients with resistance or intolerance against alternative Abl-Kinase Inhibitors (≥2nd line) (DasaHIT Trial (Dasatinib Holiday for Improved Tolerability))

Condition or Disease	Intervention/Treatment	Phase
Myeloid Leukemia, Chronic	Drug: dasatinib (SPRYCEL®)	Phase 3

Detailed Description

Dasatinib is indicated in Europe for:

• Treatment of adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase

• Chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib

• Ph+ acute lymphoblastic leukemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy Compared to imatinib, dasatinib in CML achieves faster and better responses. Dasatinib is known for its selected toxicities (fluid retention, edema, pleural effusion, and hematological toxicity) requiring dose reductions or treatment interruptions; these toxicities are more frequent in the first two years of treatment. A randomized dose optimization trial for QD dosing vs. BID dosing has demonstrated non-inferiority with regards to efficacy with an improved toxicity profile. In a pilot study, analyzing patients with dasatinib toxicity, a fixed dasatinib weekend holiday allowed safe toxicity management without impairing efficacy. Furthermore the alternated schedule was also able to improve response parameters in patients that had never achieved an acceptable response prior to the onset of dasatinib holiday dosing schedule. The biological rationale for a holiday dosing schedule is that dasatinib has shown an improved cell death of CML cells even after short exposure times; this improved cell death exceeds the killing rate observed with imatinib in vitro. In summary, the reported preclinical and clinical evidence indicates that efficacy seems to require adequate dasatinib Cmax, while low Cmin (five half-lives between doses) does not impair efficacy nor induces drug resistance. It is speculated that a weekend holiday, allowing a better tolerability, would improve patients' drug adherence. The Investigators hypothesize that a dasatinib holiday schedule (5x100mg+2x0mg weekly) compared to a regular dose (7x100mg weekly) will reduce the rate of clinically significant toxicity (e.g., fluid retention, hematological toxicity, musculoskeletal pain) by 20% observed within the first two years of treatment. The Investigators also hypothesize that the dasatinib holiday schedule is non-inferior to dasatinib regular dose in achieving the European LeukemiaNet (ELN) recommended levels of response within the first 24 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 291 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment Optimization for Patients With Chronic Myeloid Leukemia (CML) With Treatment naïve Disease (1st Line) and Patients With Resistance or Intolerance Against Alternative Abl-Kinase Inhibitors (≥2nd Line)
• Actual Study Start Date: Aug 1, 2016
• Anticipated Primary Completion Date: Mar 1, 2023
• Anticipated Study Completion Date: Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A. Standard arm 100mg dasatinib (SPRYCEL®) daily dose (QD) (7x100) (Standard therapy)	Drug: dasatinib (SPRYCEL®); Treatment optimization for patients with chronic myeloid leukemia (CML)
Experimental: B. Study arm 100mg dasatinib (SPRYCEL®) (QD) weekdays (1-5) only (5x100+2x0) (overall dose reduction per week)	Drug: dasatinib (SPRYCEL®); Treatment optimization for patients with chronic myeloid leukemia (CML)

Outcome Measures

Primary Outcome Measures

1. cumulative toxicity score [month 24]

   The cumulative toxicity score after two years of dasatinib treatment. More specifically, toxicity will be assessed taking into account both the rate of grade 2-4 toxicities and the cumulative severity of adverse events of specific interest. The following AEs of specific interest will be used to compose the cumulative toxicity score: Pleural effusion Fluid retention, other (edema, pericardial effusion, pulmonary arterial hypertension, congestive heart failure, pulmonary edema) Hematological toxicity (neutropenia, thrombocytopenia, anemia) Others (Musculoskeletal pain, skin toxicity (rash), gastrointestinal toxicity (nausea, diarrhea, abdominal pain, vomiting)

2. Rate of molecular Response [month 24]

   The co-primary endpoint of the study is: rate of major molecular response (MMR) as assessed by BCR-ABL (IS [International Score] in %) -monitoring by 24 months to safeguard non-inferiority of the test cohort.

Secondary Outcome Measures

1. Quality of life assessment [month 24]

   Quality of life assessment via Patient-Questionnaire.

2. Rate of molecular Response [6 and 12 months]

   Rate of molecular response (MMR)as assessed by BCR-ABL (IS [International Score] in %) at 6 and 12 months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph+ chromosome [t(9;22)(q34;q11)].

• Ph negative cases or patients with variant translocations who are BCR-ABL positive in multiplex PCR4 will be also considered eligible.

• ECOG performance status ≤2.

• Age ≥ 18 years old (no upper age limit is given)

• Serum levels of potassium, magnesium and total calcium within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]). Correction of electrolytes' levels with supplements to meet enrolment criteria is allowed.

• AST and ALT ≤2.5 x ULN or 5.0 x ULN if considered due to leukemia

• Alkaline phosphatase ≤2.5 x ULN unless considered due to leukemia

• Total bilirubin ≤1.5 x ULN, except known Gilbert disease

• Serum creatinine ≤2 x ULN

• Written informed consent prior to any study procedures being performed.

For 1st-line patients:

• Pre-treatment with hydroxyurea up to 6 months and imatinib or dasatinib for duration of up to 4 weeks is permitted.

For ≥ 2nd-line patients:

• Patients with treatment failure according to the 2013 ELN Recommendations criteria3 or treatment intolerance as assessed by the investigator after prior treatment with TKIs other than dasatinib (imatinib, nilotinib, bosutinib, ponatinib).

Exclusion Criteria:

• Previous allogeneic stem cell transplantation (AlloSCT)

• Known impaired cardiac function, including any of the following:

• Congenital long QT syndrome

• History of or presence of clinically significant ventricular or atrial tachyarrhythmia

• QTc >450 msec on screening ECG

• Myocardial infarction within 6 months prior to starting therapy

• Other clinical significant heart disease (e.g. unstable angina pectoris, congestive heart failure)

• Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled

• Other concurrent uncontrolled medical conditions (e.g., active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol

• Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)

• Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4

• Patients who have undergone major surgery ≤2 weeks prior to starting study drug or who have not recovered from side effects of such therapy

• Patients who are pregnant or breastfeeding or women of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of dasatinib. Post-menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of birth control throughout the study and for up to 3 months following discontinuation of study drug

• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)

• Active autoimmune disorder, including autoimmune hepatitis

• Known serious hypersensitivity reactions to dasatinib

• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention

• Patients unwilling or unable to comply with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Uniklinik der RWTH Aachen	Aachen		Germany	52074
2	Gesundheitszentrum St. Marien GmbH	Amberg		Germany	92224
3	Gemeinschaftspraxis Dres. Klausmann	Aschaffenburg		Germany	63739
4	OnkoBer	Berlin		Germany	10115
5	Evangelisches Klinikum Bethel gGmbH	Bielefeld		Germany	33611
6	Universitätsklinikum Bonn	Bonn		Germany	53111
7	Klinikum Bremen-Mitte gGmbH	Bremen		Germany	28177
8	Klinikum Chemnitz gGmbH	Chemnitz		Germany	09113
9	Gemeinschaftspraxis Mohm/Prange-Krex	Dresden		Germany	01307
10	Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden	Dresden		Germany	01307
11	Helios St. Johannes Klinik Duisburg	Duisburg		Germany	47166
12	Gemeinschaftspraxis Erlangen	Erlangen		Germany	91052
13	Universitätsklinikum Essen	Essen		Germany	45147
14	Universitätsklinikum Frankfurt	Frankfurt		Germany	60590
15	Universitätsklinikum Freiburg	Freiburg		Germany	79106
16	Katholisches Karl-Leisner Klinikum	Goch		Germany	47574
17	MVZ Onkologische Kooperation Harz	Goslar		Germany	38642
18	ConMed GmbH	Göttingen		Germany	37073
19	Hämato-Onkologische Gemeinschaftspraxis Halberstadt	Halberstadt		Germany	38820
20	Universitätsklinikum Halle/S.	Halle		Germany	06120
21	Asklepios MVZ Onkologie	Hamburg		Germany	22417
22	MediProjekt GbR	Hannover		Germany	30171
23	St. Bernward Krankenhaus Hildesheim	Hildesheim		Germany	31134
24	Universitätsklinikum Jena	Jena		Germany	07740
25	Institut für med. Dokumentation, Gutachtenstellung, Gesundheitsförderung und Qualitätssicherung GbR	Kaiserslautern		Germany	67655
26	Städtisches Klinikum Karlsruhe gGmbH	Karlsruhe		Germany	76133
27	St. Vincentius-Kliniken Karlsruhe	Karlsruhe		Germany	76137
28	Onkologische Gemeinschaftspraxis	Kassel		Germany	34119
29	Klinikum Kassel	Kassel		Germany	34125
30	Städtisches Krankenhaus Kiel GmbH	Kiel		Germany	24116
31	Universitätsklinikum Schleswig-Holstein	Kiel		Germany	24116
32	InVo Institut für Versorgungsforschung	Koblenz		Germany	56068
33	MVZ Hämatologie und Onkologie	Krefeld		Germany	47805
34	Onkologische Schwerpunktpraxis	Kronach		Germany	96317
35	Onkologisches Zentrum	Lebach		Germany
36	Studienzentrum UnterEms	Leer		Germany	26789
37	Universitätsklinikum Leipzig	Leipzig		Germany	04103
38	Universitätsmedizin Mannheim	Mannheim		Germany	68169
39	Universitätsklinikum Gießen und Marburg GmbH	Marburg		Germany	35043
40	Stauferklinikum Schwäbisch Gmünd	Mutlangen		Germany	73557
41	Rotkreuzklinikum München	München		Germany	80634
42	Gemeinschaftspraxis Hämatologie/ Onkologie	München		Germany	81241
43	Universitätsklinikum Münster	Münster		Germany	48149
44	Hämatologisch-onkologische Schwerpunktpraxis	Neustadt Am Rübenberge		Germany	31535
45	Klinikum Passau	Passau		Germany	94032
46	Kreiskliniken Reutlingen GmbH	Reutlingen		Germany	72764
47	Universitätsmedizin Rostock	Rostock		Germany	18057
48	Klinikum Südstadt Rostock	Rostock		Germany	18059
49	Hämatologie-Onkologie Stolberg	Stolberg		Germany	52222
50	Klinikum Mutterhaus der	Trier		Germany	54290
51	Universitätsklinikum Ulm	Ulm		Germany	89081
52	Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH	Villingen-Schwenningen		Germany	78052
53	Rems-Murr-Klinik Winnenden	Winnenden		Germany	71364

Sponsors and Collaborators

• University of Jena

Investigators

• Principal Investigator: Andreas Hochhaus, Prof., Jena University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Prof. Dr. med. Andreas Hochhaus, Director of the Clinic of Internal Medicine II, University of Jena
• ClinicalTrials.gov Identifier: NCT02890784
• Other Study ID Numbers: DasaHIT
• First Posted: Sep 7, 2016
• Last Update Posted: Jun 2, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Dasatinib

Study Results

No Results Posted as of Jun 2, 2022