A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL

Sponsor

Acerta Pharma BV (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02970318

Collaborator

(none)

311

Enrollment

157

Locations

Arms

115

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is designed to evaluate the efficacy of acalabrutinib compared with rituximab in combination with idelalisib or bendamustine in previously treated subjects with chronic lymphocytic leukemia (CLL).

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Acalabrutinib (ACP-196) Drug: Rituximab Drug: Idelalisib Drug: Bendamustine	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

311 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official 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 R/R Chronic Lymphocytic Leukemia

Actual Study Start Date :

Feb 2, 2017

Actual Primary Completion Date :

Sep 3, 2021

Anticipated Study Completion Date :

Sep 3, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Acalabrutinib (ACP-196) Acalabrutinib (ACP-196) Monotherapy	Drug: Acalabrutinib (ACP-196) Acalabrutinib monotherapy
Active Comparator: Rituximab Plus Idelalisib or Bendamustine Investigator's Choice of Rituximab Plus Idelalisib or Bendamustine	Drug: Rituximab Rituximab in combination with idelalisib or bendamustine Drug: Idelalisib Idelalisib in combination with rituximab Drug: Bendamustine Bendamustine in combination with rituximab

Arm

Intervention/Treatment

Experimental: Acalabrutinib (ACP-196)

Acalabrutinib (ACP-196) Monotherapy

Drug: Acalabrutinib (ACP-196)

Acalabrutinib monotherapy

Active Comparator: Rituximab Plus Idelalisib or Bendamustine

Investigator's Choice of Rituximab Plus Idelalisib or Bendamustine

Drug: Rituximab

Rituximab in combination with idelalisib or bendamustine

Drug: Idelalisib

Idelalisib in combination with rituximab

Drug: Bendamustine

Bendamustine in combination with rituximab

Outcome Measures

Primary Outcome Measures

IRC-assessed progression-free survival (PFS) in Arm A compared to Arm B [48 months]
PFS, defined as the time from date of randomization to date of IRC-assessed disease progression or death due to any cause, whichever comes first. Response is per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 20008 criteria (Hallek, et al), with clarification for treatment-related lymphocytosis (Cheson et al) 2012.

Secondary Outcome Measures

1. Investigator-assessed progression-free survival (PFS) in Arm A compared to Arm B [48 months]
PFS, defined as the time from date of randomization to date of IRC-assessed disease progression or death due to any cause, whichever comes first. Response is per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 20008 criteria (Hallek, et al), with clarification for treatment-related lymphocytosis (Cheson et al) 2012.
2. Investigator and IRC-assessed overall response rate (ORR) in Arm A compared to Arm B [48 months]
ORR is defined as best response of complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response as assessed by the IRC and Investigator, on or before initiation of subsequent anticancer therapy.
3. Overall survival (OS) in Arm A compared to Arm B [48 months]
OS is defined as the time from date of randomization to death due to any cause.
4. Patient reported outcomes (PROs) in Arm A compared to Arm B [48 months]
PROs are based on Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue). PROs are not collected with Protocol Amendment Version 6.
5. Investigator and IRC-assessed duration of response (DOR) in Arm A compared to Arm B [48 months]
DOR is defined as the interval from first documentation of Investigator and IRC-assessed CR, CRi, nPR or PR, to first documentation of disease progression or death from any cause, whichever is earlier.
6. Time to next treatment (TTNT) in Arm A compared to Arm B [48 months]
TTNT is defined as the time from date of randomization to the date of institution of non-protocol specified treatment for CLL (or first dose of acalabrutinib for Arm B subjects who crossed over to receive acalabrutinib) or death due to any cause, whichever comes first.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Men and women ≥ 18 years of age.
ECOG performance status of 0 to 2.
Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008):
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.
Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
Presence of ≥ 5 x 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since initial diagnosis).
Must have documented CD20-positive CLL.
Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
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).
Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
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 10^9/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 (e.g., infections) should be excluded.
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
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:

Unintentional weight loss ≥ 10% within the previous 6 months before screening.

Significant fatigue (ECOG performance score 2; inability to work or perform usual activities).
Fevers higher than 100.5°F or 38.0°C for ≥ 2 weeks before screening without evidence of infection.
Night sweats for > 1 month before screening without evidence of infection.

Meet the following laboratory parameters:
ANC ≥ 750 cells/μL (0.75 x 10^{9/L), or ≥ 500 cells/μL (0.50 x 10}9/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.
Platelet count ≥ 50,000 cells/μL (50 x 10^{9/L), or ≥ 30,000 cells/μL (30 x
10}9/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 10^9/L).
Serum AST and ALT ≤ 2.0 x ULN.
Total bilirubin ≤ 1.5 x ULN.
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].
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.
Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib, 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. Highly effective forms of contraception are defined in Section 9.2.5.
Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. Highly effective forms of contraception are defined in Section 9.2.5.
Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules without difficulty.
Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

Exclusion Criteria:

Known CNS lymphoma or leukemia.
Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
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).
Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199) or a BCR inhibitor (e.g., BTK inhibitors or PI3K inhibitors). Prior bendamustine is allowed if Investigator's choice for treatment in Arm B is idelalisib with rituximab. Bendamustine retreatment is allowed if the prior response to bendamustine lasted > 24 months.
Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
Corticosteroid use > 20 mg daily prednisone equivalent 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.
Prior radio- or toxin-conjugated antibody therapy.
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 receiving treatment for graft-vs-host disease.
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.
History of prior malignancy except for the following:
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.
Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.
Adequately treated carcinoma in situ without current evidence of disease.
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 QTc > 480 msec (calculated using Fridericia's formula: QT/RR^0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
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.
Received a live virus vaccination within 28 days of first dose of study drug.
Known history of infection with HIV or any uncontrolled active systemic infection (e.g., bacterial, viral, or fungal). For study sites in Germany: active infection with human immunodeficiency virus (seropositivity for HIV-1 or HIV-2 antibodies, and if positive, reactivity against the HIV-specific p24 antigen).
Active CMV infection (active viremia as evidenced by positive polymerase chain reaction [PCR] result for CMV DNA).
Serologic status reflecting active hepatitis B or C infection.
Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before randomization. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded.
Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
History of or ongoing drug-induced pneumonitis.
History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
Requires treatment with a strong CYP3A inhibitor/inducer.
Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
Breast feeding or pregnant.
Concurrent participation in another therapeutic clinical trial.
Prothrombin time/INR or aPTT (in the absence of a Lupus anticoagulant) > 2.0 x ULN. Exception: Subjects receiving warfarin are excluded, however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor.
History of confirmed progressive multifocal leukoencephalopathy (PML)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chandler	Arizona	United States	85224
2	Research Site	Oxnard	California	United States	93030
3	Research Site	Athens	Georgia	United States	30607
4	Research Site	Joliet	Illinois	United States	60435
5	Research Site	Cedar Rapids	Iowa	United States	52403
6	Research Site	Mount Sterling	Kentucky	United States	40353
7	Research Site	Saint Cloud	Minnesota	United States	56303
8	Research Site	Lincoln	Nebraska	United States	68506
9	Research Site	Brick	New Jersey	United States	08724
10	Research Site	Nyack	New York	United States	10960
11	Research Site	Canton	Ohio	United States	44719
12	Research Site	Fort Sam Houston	Texas	United States	78234
13	Research Site	Round Rock	Texas	United States	78665
14	Research Site	Adelaide		Australia	5000
15	Research Site	Box Hill		Australia	3128
16	Research Site	Frankston		Australia	3199
17	Research Site	Geelong		Australia	3220
18	Research Site	Gosford		Australia	2250
19	Research Site	Hobart		Australia	7000
20	Research Site	Kogarah		Australia	2217
21	Research Site	Murdoch		Australia	6150
22	Research Site	Nedlands		Australia	6009
23	Research Site	South Brisbane		Australia	4101
24	Research Site	Woodville		Australia	5011
25	Research Site	Linz		Austria	4010
26	Research Site	Salzburg		Austria	5020
27	Research Site	Wels		Austria	4600
28	Research Site	Wien		Austria	1130
29	Research Site	Wien		Austria	1160
30	Research Site	Antwerpen		Belgium	2060
31	Research Site	Ghent		Belgium	9000
32	Research Site	Roeselare		Belgium	8900
33	Research Site	Yvoir		Belgium	5530
34	Research Site	Pleven		Bulgaria	5800
35	Research Site	Plovdiv		Bulgaria	4002
36	Research Site	Stara Zagora		Bulgaria	6000
37	Research Site	Vratsa		Bulgaria	3000
38	Research Site	Barrie	Ontario	Canada	L4M 6M2
39	Research Site	Calgary		Canada	T2N 2T9
40	Research Site	Montreal		Canada	H3T 1E2
41	Research Site	Ottawa		Canada	K1H 8L6
42	Research Site	Regina		Canada	S4T 7T1
43	Research Site	Saint John		Canada	E2L 4L2
44	Research Site	Toronto		Canada	M4N 3M5
45	Research Site	Toronto		Canada	M5G 2M9
46	Research Site	Zadar		Croatia	23 000
47	Research Site	Zagreb		Croatia	10 000
48	Research Site	Brno		Czechia	625 00
49	Research Site	Novy Hradec Kralove		Czechia	500 05
50	Research Site	Olomouc		Czechia	779 00
51	Research Site	Ostrava Poruba		Czechia	708 52
52	Research Site	Plzen - Lochotin		Czechia	304 60
53	Research Site	Praha 10		Czechia	100 34
54	Research Site	Bordeaux		France	33076, FR
55	Research Site	Brest		France	29609
56	Research Site	Montpellier		France	34295
57	Research Site	Nantes cedex 1		France	44093
58	Research Site	Paris cedex 13		France	75651
59	Research Site	Paris		France	75010
60	Research Site	Perpignan		France	66000
61	Research Site	Provence Alpes Cote D'Azur		France	13273
62	Research Site	Rennes Cedex		France	35000
63	Research Site	Rouen		France	76038
64	Research Site	Aschaffenburg		Germany	63739
65	Research Site	Dresden		Germany	1307
66	Research Site	Munchen		Germany	81377
67	Research Site	Mutlangen		Germany	73557
68	Research Site	Ulm		Germany	89081
69	Research Site	HongKong		Hong Kong	150001
70	Research Site	Pok Fu Lam		Hong Kong
71	Research Site	Budapest		Hungary	1122
72	Research Site	Debrecen		Hungary	4032
73	Research Site	Gyula		Hungary	5700
74	Research Site	Kaposvár		Hungary	7400
75	Research Site	Ashkelon		Israel	7830604
76	Research Site	Haifa		Israel	34362
77	Research Site	Jerusalem		Israel	9112001
78	Research Site	Kfar Saba		Israel	4428164
79	Research Site	Nahariya		Israel	22100
80	Research Site	Petah Tikvah		Israel	49102
81	Research Site	Aviano		Italy	33081
82	Research Site	Bergamo		Italy	24127
83	Research Site	Brescia		Italy	25123
84	Research Site	Firenze		Italy	50134
85	Research Site	Genova		Italy	16126
86	Research Site	Genova		Italy	16132
87	Research Site	Meldola		Italy	47014
88	Research Site	Milano		Italy	20132
89	Research Site	Milan		Italy	20162
90	Research Site	Modena		Italy	41100
91	Research Site	Busan		Korea, Republic of	49241
92	Research Site	Daegu		Korea, Republic of	41944
93	Research Site	Dong-gu		Korea, Republic of	44033
94	Research Site	Gyeonggi-do		Korea, Republic of	13620
95	Research Site	Incheon		Korea, Republic of	UNK
96	Research Site	Jeonju-si		Korea, Republic of	54907
97	Research Site	Seoul		Korea, Republic of	3080
98	Research Site	Seoul		Korea, Republic of	3722
99	Research Site	Addington		New Zealand	8011
100	Research Site	Dunedin		New Zealand	9016
101	Research Site	Palmerston North		New Zealand	4442
102	Research Site	Tauranga		New Zealand	3112
103	Research Site	Bialystok		Poland	15-276
104	Research Site	Bydgoszcz		Poland	85-168
105	Research Site	Gdansk		Poland	80-129
106	Research Site	Krakow		Poland	30-510
107	Research Site	Lodz		Poland	93-510
108	Research Site	Lublin		Poland	20-081
109	Research Site	Woj. Podkarpackie		Poland	36-200
110	Research Site	Novosibirsk		Russian Federation	630087
111	Research Site	Obninsk		Russian Federation	249031
112	Research Site	Penza		Russian Federation	440008
113	Research Site	Ryazan		Russian Federation	390000
114	Research Site	Sochi		Russian Federation	Unk
115	Research Site	St. Petersburg		Russian Federation	194044
116	Research Site	St. Petersburg		Russian Federation	197341
117	Research Site	Tula		Russian Federation	300053
118	Research Site	Volgograd		Russian Federation	Unk
119	Research Site	Yaroslavl		Russian Federation	150023
120	Research Site	Yekaterinburg		Russian Federation	620072
121	Research Site	SGP		Singapore	169608
122	Research Site	SGP		Singapore	188770
123	Research Site	SGP		Singapore	217562
124	Research Site	Bratislava		Slovakia	833 10
125	Research Site	Kosice		Slovakia	040 01
126	Research Site	Badalona		Spain	8916
127	Research Site	Madrid		Spain	28006
128	Research Site	Madrid		Spain	28009
129	Research Site	Madrid		Spain	28031
130	Research Site	Madrid		Spain	28033
131	Research Site	Madrid		Spain	28041
132	Research Site	Majadahonda		Spain	28222
133	Research Site	Salamanca		Spain	37007
134	Research Site	Santander		Spain	39008
135	Research Site	Valencia		Spain	46026
136	Research Site	Goeteborg		Sweden	413 46
137	Research Site	Lulea		Sweden	97180
138	Research Site	Stockholm		Sweden	171 76
139	Research Site	Hualien		Taiwan	970
140	Research Site	Tainan		Taiwan	70403
141	Research Site	Taipei		Taiwan	100
142	Research Site	Cherkasy		Ukraine	18009
143	Research Site	Dnipropetrovsk		Ukraine	49102
144	Research Site	Ivano-Frankivsk		Ukraine
145	Research Site	Khmelnytsky		Ukraine	29000
146	Research Site	Kyiv		Ukraine	03022
147	Research Site	Kyiv		Ukraine
148	Research Site	Zhytomir		Ukraine	10002
149	Research Site	Birmingham		United Kingdom	B9 5SS
150	Research Site	Cambridge		United Kingdom	CB2 0QQ
151	Research Site	Canterbury		United Kingdom	CT1 3NG
152	Research Site	Leicester		United Kingdom	LE1 7RH
153	Research Site	London		United Kingdom	SE5 9RS
154	Research Site	Maidstone		United Kingdom	ME16 9QQ
155	Research Site	Manchester		United Kingdom	M20 4BX
156	Research Site	Southampton		United Kingdom	SO16 6YD
157	Research Site	Wolverhampton		United Kingdom	WV10 0QP