A trial to see the effects of increased doses of ACP-196 (the test drug) in subjects with Leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acerta Pharma B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 May 2015 → ongoing

Decision date (initial)

2024-09-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ACERTA PHARMA, BV

External identifiers

EU CT number

2023-509346-35-00

EudraCT number

2014-000440-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Dose response, Therapy, Pharmacodynamic, Efficacy

1. Establish the safety and the MTD of orally administered acalabrutinib in subjects with CLL/SLL
2. Determine the PK of orally administered acalabrutinib and identification of its major metabolite

Secondary objectives 1

1. Evaluate tumor response by ORR, DOR and PFS.

Conditions and MedDRA coding

Richter's Syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Men and women ≥ 18 years of age with a confirmed diagnosis of CLL/SLL, which has relapsed after, or been refractory to, ≥ 2 previous treatments for CLL/SLL.
2. Must have measurable CLL/SLL defined as ≥ 1 lymph node ≥ 2 cm as measured in the longest diameter.
3. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: o 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). o Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. o Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (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 (e.g., infections) should be excluded. o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. o 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.  - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.  - Night sweats for > 1 month before screening without evidence of infection.
4. ECOG performance status of ≤ 2
5. Agreement to use highly effective methods of contraception during the study and for 2 days after the last dose of study drug if sexually active and able to bear or beget children.
6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules or tablets without difficulty.
7. 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 subject privacy regulations).
8. Inclusion Criteria for Treatment Subgroups: Treatment Naive only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL, who require treatment per National Cancer Institute or International Working Group guidelines and a) do not want to receive chemoimmunotherapy or b) have comorbidities that would preclude chemoimmunotherapy.
9. For Treatment Subgroups: Ibrutinib Intolerant only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL who are not tolerating ibrutinib due to ibrutinib-related AEs.
10. For Treatment Subgroups: Richter's Syndrome and Prolymphocytic Leukemia Transformation only: Men and women ≥ 18 years of age with biopsy proven DLBCL Richter's transformation or prolymphocytic leukemia transformation
11. For Treatment Subgroups: Ibrutinib R/R only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL whose best response after 2 cycles of ibrutinib therapy was SD or nonresponse or who initially responded to ibrutinib therapy and now have signs of clinical progression

Exclusion criteria 26

1. Prior malignancy, except for adequately treated basal cell, squamous cell skin cancer or in situ cervical cancer. Subjects with other prior malignancies from which the subject has been disease free for ≥ 2 years may be included if approved by the medical monitor
2. A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
3. Significant cardiovascular disease such as uncontrolled or 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 left ventricular ejection fraction (LVEF) ≤ 40%.
4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
5. Any immunotherapy within 4 weeks of first dose of study drug.
6. For subjects with recent chemotherapy or experimental therapy the first dose of study drug must occur after 5 times the half-life of the agent(s).
7. Relapsed after, or refractory to, prior BTK inhibitor therapy (Note: Does not apply to Ibrutinib R/R or Richter's Syndrome Group).
8. Any history of Richter's transformation (Note: Does not apply to Richter's Syndrome Group).
9. Central nervous system (CNS) involvement by lymphoma
10. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation
11. Known history of human immunodeficiency virus (HIV) or serologic status indicating active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection or any uncontrolled active systemic infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
12. 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 daily or equivalent).
13. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug
14. Requires treatment with proton pump inhibitors [PPIs] (e.g.,omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: this criterion no longer applies to patients who have switched from acalabrutinib capsules to tablets.
15. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug
16. Major surgery within 4 weeks before first dose of study drug
17. ANC < 0.75 x 109/L or platelet count < 50 x 109/L unless there is bone marrow involvement
18. Total bilirubin > 1.5 x ULN (total bilirubin ≤ 2.5 x ULN allowed in subjects with autoimmune hemolytic anemia that is otherwise controlled); AST or ALT > 3.0 x ULN unless disease related.
19. Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN.
20. Significant screening ECG abnormalities including 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, or QTc ≥ 480 ms
21. Cardiac troponin I levels above the limit of normal as specified by the manufacturer.
22. Breast feeding or pregnant
23. History of bleeding diathesis (e.g. hemophilia, von Willebrand disease).
24. Concurrent participation in another therapeutic clinical trial
25. 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].
26. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Efficacy Parameters • Overall response rate • Duration of response • Progression-free survival (with a subgroup analysis by sex, male vs female for overall response rate, duration of response)
2. Safety Parameters • DLTs and MTD • Frequency, severity, and attribution of adverse events (AEs)
3. Pharmacokinetic and Pharmacodynamic Parameters The occupancy of BTK by acalabrutinib will be measured in peripheral blood mononuclear cells (PBMCs) with the aid of a biotin-tagged acalabrutinib analogue probe. The effect of acalabrutinib on biologic markers of B-cell function will also be evaluated

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acerta Pharma B.V.

Sponsor organisation

Acerta Pharma B.V.

Address

Kloosterstraat 9

City

Oss

Postcode

5349 AB

Country

Netherlands

Scientific contact point

Organisation

Acerta Pharma B.V.

Contact name

Global Clinical Lead

Public contact point

Organisation

Acerta Pharma B.V.

Contact name

Global Clinical Lead

Third parties 2

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications