A Clinical trial to compare Acalabrutinib (ACP-196) versus investigator's choice standard treatment with Bendamustine/Rituximab or Idelalisib/Rituximab alone in patients with with Relapsed or Refractory Chronic Lymphocytic Leukemia

• Register: EUCTR
• Last refreshed on: 12 February 2018
• Main ID: EUCTR2015-004454-17-HU
• Date of registration: 25/08/2016
• Prospective Registration: Yes
• Primary sponsor: Acerta Pharma BV
• Public title: A Clinical trial to compare Acalabrutinib (ACP-196) versus investigator's choice standard treatment with Bendamustine/Rituximab or Idelalisib/Rituximab alone in patients with with Relapsed or Refractory Chronic Lymphocytic Leukemia
• Scientific title: A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator’s Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia
• Date of first enrolment: 19/10/2016
• Target sample size: 306
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004454-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: yes; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czech Republic, Denmark, France, Germany, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, New Zealand, Poland, Romania, Russian Federation, Singapore, Slovakia, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Medical Director
• Affiliation: Acerta Pharma

• Name: Medical Director
• Affiliation: Acerta Pharma

Key inclusion & exclusion criteria

Inclusion criteria:
1. Men and women = 18 years of age.
2. ECOG performance status of 0 to 2.
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008):
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing = 1 B-cell marker (CD19, CD20, or CD23) and CD5.
b. Prolymphocytes may comprise = 55% of blood lymphocytes.
c. Presence of = 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any point since initial diagnosis).
4.Must have documented CD20-positive CLL.
5.Active disease meeting = 1 of the following IWCLL 2008 criteria for requiring treatment:
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/µL).
b. Massive (ie, = 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
c. Massive nodes (ie, = 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a LDT of < 6 months. LDT may be obtained by linear regression extrapolation of ALC obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 x 109/L (30,000/µL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
f. Constitutional symptoms documented in the subject’s chart with supportive objective measures, as appropriate, defined as = 1 of the following disease- related symptoms or signs:
i. Unintentional weight loss = 10% within the previous 6 months before screening.
ii. Significant fatigue (ECOG performance score 2; inability to work or perform usual activities).
iii. Fevers higher than 100.5°F or 38.0°C for = 2 weeks before screening without evidence of infection.
iv. Night sweats for > 1 month before screening without evidence of infection.
6. Meet the following laboratory parameters:
a. Absolute neutrophil count (ANC) = 750 cells/µL (0.75 x 109/L), or = 500 cells/µL (0.50 x 109/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.
b. Platelet count = 50,000 cells/µL (50 x 109/L), or = 30,000 cells/µL
(30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. If an Investigator has chosen bendamustine/rituximab as the Arm B treatment, platelets must be = 75,000 cells/µL (75 x 109/L).
c. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.0 x upper limit of normal (ULN).
d. Total bilirubin = 1.5 x ULN.
e. Estimated creatinine clearance of = 30 mL/min, calculated using the formula of Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female].
7.Must have received = 1 prior systemic therapies for CLL. Note: Single-agent steroids or localized radiation are not considered a prior line of therapy. If a single- agent anti-CD20 antibody was previously administered, subjects must have received = 2 doses.
8.Women who are sexually active and can bear children must agree to use highly effective form
Exclusion criteria:
1.Known CNS lymphoma or leukemia.
2.Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome.
3.Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone or equivalent).
4.Prior exposure to a BCL-2 inhibitor (eg, venetoclax/ABT-199) or a BCR inhibitor (eg, Btk inhibitors or PI3K inhibitors).
5.Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
6.Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded.
7.Prior radio- or toxin-conjugated antibody therapy.
8.Prior allogeneic stem cell transplant or prior autologous transplant within 6 months of first dose of study drug(s) or presence of graft-vs-host disease or recieving treatment for
graft-vs-host disease.
9.Major surgical procedure within 30 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
10.History of prior malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician.
b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.
c. Adequately treated carcinoma in situ without current evidence of disease.
11.Significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec (calculated using Fridericia's formula: QT/RR0.33) at screening. 12. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 13.Received a live virus vaccination within 28 days of first dose of study drug.
14.Known history of infection with HIV or any uncontrolled active systemic infection (eg, bacterial, viral or fungal).
15.Active cytomegalovirus (CMV) infection (active viremia as evidenced
by positive polymerase chain reaction [PCR] result for CMV DNA)
16.Serologic status reflecting active hepatitis B or C infection. a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative PCR result before randomization. b.Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. 17

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsed or Refractory Chronic Lymphocytic Leukemia
MedDRA version: 20.1 Level: LLT Classification code 10008978 Term: Chronic lymphocytic leukemia refractory System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Acalabrutinib
Product Code: ACP-196
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ACALABRUTINIB
CAS Number: 1420477-60-6
Current Sponsor code: ACP-196
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Zydelig® (idelalisib) 100 mg
Product Name: Idelalisib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: IDELALISIB
CAS Number: 870281-82-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Zydelig® (idelalisib) 150 mg
Product Name: Idelalisib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: IDELALISIB
CAS Number: 870281-82-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Trade Name: MabThera® (rituximab) 500 mg
Product Name: Rituximab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Levact® (bendamustine hydrochloride), powder for concentrate for infusion
Product Name: Bendamustine
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE
CAS Number: 3543-75-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Bendamustine hydrochloride Accord 2.5 mg/ml Powder for concentrate for solution for infusion
Product Name: Bendamustine
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE
CAS Number: 3543-75-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Main Objective: To evaluate the efficacy of acalabrutinib monotherapy (Arm A) compared with idelalisib/rituximab or bendamustine/rituximab (Arm B) based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Hallek 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012)—hereafter referred to as IWCLL 2008 criteria in subjects with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

Secondary Objective: To evaluate Arm A (acalabrutinib) compared with Arm B (idelalisib/rituximab or bendamustine/rituximab) in terms of:
• Investigator (INV)-assessed PFS per IWCLL 2008 criteria.
• INV- and IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria.
• Overall survival (OS).
• Patient-reported outcomes (PROs) by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue).
• INV- and IRC-assessed duration of response (DOR).
• Time to next treatment (TTNT).

Primary end point(s): The primary endpoint of the study is PFS (defined as the time from randomization until disease progression or death from any cause) as assessed by the IRC per IWCLL 2008 criteria.

Timepoint(s) of evaluation of this end point: Estimated 48 months

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Estimated 48 months

Secondary end point(s): • INV-assessed PFS per IWCLL 2008 criteria.
• INV-assessed ORR (defined as the proportion of patients who achieve a best response of complete remission [CR], complete remission with incomplete bone marrow recovery [CRi], nodal partial remission [nPR], or partial remission [PR]) per IWCLL 2008 criteria.
• IRC-assessed ORR per IWCLL 2008 criteria.
• OS (defined as the time from randomization to the date of death due to any cause)
• PROs as measured by change in scores from baseline to each assessment in the FACIT-Fatigue.
• INV- and IRC-assessed DOR (defined as the time from the first documentation of objective response to the earlier time of disease progression [assessed by the IRC per IWCLL 2008 criteria] or death from any cause)
• TTNT (defined as the time from randomization to institution of
nonprotocol-specified treatment for CLL)

Secondary ID(s)

2015-004454-17-BE

ACE-CL-309

Source(s) of Monetary Support

Acerta Pharma