Acalabrutinib, Obinutuzumab and Chlorambucil in Treatment naïve CLL (ElevateTN)

• ClinicalTrials.gov Identifier: NCT02475681
• Recruitment Status: Active, not recruiting
• First Posted: June 19, 2015
• Results First Posted: January 10, 2023
• Last Update Posted: March 4, 2024
• Sponsor: Acerta Pharma BV
• Information provided by (Responsible Party): Acerta Pharma BV

Tracking Information

• First Submitted Date: June 12, 2015
• First Posted Date: June 19, 2015
• Results First Submitted Date: February 28, 2020
• Results First Posted Date: January 10, 2023
• Last Update Posted Date: March 4, 2024
• Actual Study Start Date: June 26, 2015
• Actual Primary Completion Date: February 8, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 15, 2022)

Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B [ Time Frame: IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months. ]

To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first.

• Original Primary Outcome Measures (submitted: June 16, 2015): Progression-free survival in Arm A compared to Arm B [ Time Frame: 49 months ]

Current Secondary Outcome Measures (submitted: December 15, 2022)

• Progression-free Survival by IRC Assessment Arm A Versus Arm C [ Time Frame: IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months. ]
  To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib monotherapy (Arm C) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first.
• IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C [ Time Frame: IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months. ]
  ORR was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, or PR at or before initiation of subsequent anticancer therapy. ORR including PRL was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, PR or PRL at or before initiation of subsequent anticancer therapy
• Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C [ Time Frame: From randomization date to start of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first assessed up to 40 months of follow-up. ]
  TTNT was defined as the time from randomization to start date of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first. TTNT was analyzed in the same fashion as that for the primary efficacy analysis
• Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C [ Time Frame: From randomization date until death, withdrawal by subject, lost to follow-up, or by analysis data cut off date on 08Feb2019 whichever comes first up to 40 months of follow-up. ]
  OS was defined as the time from the date of randomization to death due to any cause.

Original Secondary Outcome Measures (submitted: June 16, 2015)

• IRC-assessed objective response rate (ORR) in Arm A versus Arm B and Arm A versus Arm C [ Time Frame: 49 months ]
• Time to next treatment (TTNT) in Arm A versus Arm B and Arm A versus Arm C [ Time Frame: 49 months ]
• Incidence of adverse events, serious adverse events and changes in laboratory measurements in Arm A versus Arm B and Arm A versus Arm C [ Time Frame: 49 months ]
• Overall survival in Arm A versus Arm B and Arm A versus Arm C [ Time Frame: 49 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Acalabrutinib, Obinutuzumab and Chlorambucil in Treatment naïve CLL
• Official Title: A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of Obinutuzumab in Combination With Chlorambucil, Acalabrutinib (ACP-196) in Combination With Obinutuzumab, and Acalabrutinib Monotherapy in Subjects With Previously Untreated CLL

Brief Summary

This Primary objective is evaluating the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) for the treatment of previously untreated chronic lymphocytic leukemia (CLL). Secondary objectives: 1) To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C) based on IRC assessment of PFS per IWCLL 2008 criteria.

2)To compare obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib plus obinutuzumab (Arm B) and obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C) in terms of: IRC-assessed objective response rate (ORR); Tine to next treatment (TTNT); Overall Survival (OS)

Detailed Description

ELEVATE-TN is a global, phase 3, multicenter, open-label study in patients with treatment-naive chronic lymphocytic leukemia (CLL). Study enrollment is completed. The study randomized a total of 535 subjects in 142 study sites in 18 countries between 14 September 2015 through 08 February 2017. Patients were randomly assigned to receive Acalabrutinib and Obinutuzumab, Acalabrutinib monotherapy, or Obinutuzumab and oral Chlorambucil. The primary endpoint was progression-free survival between the two combination-therapy groups, defined as the time from randomization until disease progression by use of iwCLL 2008 criteria, or death, assessed by independent review committee (IRC). Crossover to Acalabrutinib was allowed in patients who progressed on Obinutuzumab-Chlorambucil.

The results of this study provide new evidence for therapy in patients with treatment-naive chronic lymphocytic leukemia by showing the efficacy of Acalabrutinib used with or without Obinutuzumab compared with chemoimmunotherapy.

Currently the study is in maintenance phase, with more than 430 subjects on study, to generate more evidence. We are not expecting any significant change in the near future.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Lymphocytic Leukemia

Intervention

• Drug: Acalabrutinib
  Other Name: ACP-196 (Calquence)
• Drug: Obinutuzumab
  Other Name: GAZYVA / GAZYVARO
• Drug: Chlorambucil
  Other Name: LEUKERAN

Study Arms

• Active Comparator: Arm A - Obinutuzumab in Combination with Chlorambucil
  Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles starting at Cycle 1 Day 1. Chlorambucil will be orally administered on Days 1 and 15 of Cycles 1 through 6.
  Interventions:

  • Drug: Obinutuzumab
  • Drug: Chlorambucil
• Experimental: Arm B - Acalabrutinib in Combination with Obinutuzumab
  Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles starting at Cycle 2 Day 1. Acalabrutinib (ACP-196) will be orally administered starting on Cycle 1 Day 1. Daily administration of Acalabrutinib (ACP-196) will continue until disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Acalabrutinib
  • Drug: Obinutuzumab
• Experimental: Arm C - Acalabrutinib Monotherapy
  Acalabrutinib (ACP-196) will be orally administered on Cycle 1 Day 1 until disease progression or unacceptable toxicity.
  Intervention: Drug: Acalabrutinib

• Publications *: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2. Erratum In: Lancet. 2020 May 30;395(10238):1694.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 14, 2017): 535
• Original Estimated Enrollment (submitted: June 16, 2015): 510
• Estimated Study Completion Date: September 30, 2025
• Actual Primary Completion Date: February 8, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Men and women:

   a. ≥ 65 years of age OR b. > 18 and < 65 years of age, provided that they meet at least one of the following criteria: i. Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation ii. A score higher than 6 on the CIRS-G (Appendix L).

2. ECOG performance status of 0, 1, or 2.

3. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008):

   1. 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.
   2. Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
   3. Presence of ≥ 5 x 109 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis)

4. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:

   1. 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).
   2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
   3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
   4. 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 (e.g., infections) should be excluded.
   5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
   6. 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 (i.e., ECOG performance status 2; inability to work or perform usual activities).

   iii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.

   iv. Night sweats for > 1 month before Screening without evidence of infection.

5. This criterion was deleted as of Protocol Amendment 3.

6. Meet the following laboratory parameters:

   1. 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.
   2. 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.
   3. Serum AST and ALT/SGPT ≤ 3.0 x ULN.
   4. Total bilirubin ≤ 1.5 x ULN.
   5. Estimated creatinine clearance (i.e., eGFR using Cockcroft-Gault) ≥ 30 mL/min
7. Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations.
8. 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 or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. Highly effective forms of contraception are defined in Section 6.4.4.
9. 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 obinutuzumab or chlorambucil, whichever is later. Highly effective forms of contraception are defined in Section 6.4.4.
10. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later.
11. Must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations). Note vulnerable subjects, as defined in International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol (e.g., prisoners or institutionalized subjects).

Exclusion Criteria:

1. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed).
2. Known CNS lymphoma or leukemia.
3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
4. Missing or incomplete documentation of FISH results reflecting the presence or absence of 17p del and the percentage of cells with the deletion in subject records before randomization.
5. 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).
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 WBC count lowering are excluded.
7. Major surgery within 4 weeks before first dose of study drug.

8. History of prior malignancy except for the following:

   1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician.
   2. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer.
   3. Adequately treated cervical carcinoma in situ without current evidence of disease.
9. 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 QTc > 480 msec at screening.
10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
11. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective treatment.
12. Known history of infection with HIV. 13. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

14. Serologic status reflecting active hepatitis B or C 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 randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.

15. History of stroke or intracranial hemorrhage within 6 months before randomization.

16. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.

18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

19. Breast feeding or pregnant. 20. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk.

21. Concurrent participation in another therapeutic clinical trial. 22. Requires treatment with a strong CYP3A inhibitor/inducer. 23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, Chile, Colombia, France, Germany, Hungary, Israel, Italy, Lithuania, New Zealand, Poland, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02475681
• Other Study ID Numbers: ACE-CL-007; 2014-005582-73 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: Acerta Pharma BV
• Original Responsible Party: Same as current
• Current Study Sponsor: Acerta Pharma BV
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: AstraZeneca Clinical Study Information Center; 1-877-240-9479 information.center@astrazeneca.com

• PRS Account: Acerta Pharma BV
• Verification Date: February 2024