E-Newsletter - March 2019
Spotlight on Alliance Trials

Alliance Trial Seeks to IMPROVE Standard of Care for Initial Therapy of Older Adults with Chronic Lymphocytic Leukemia

Alliance A041702 - A randomized phase III study of ibrutinib plus obinutuzumab versus ibrutinib plus venetoclax and obinutuzumab in untreated older patients (>70 years of age) with chronic lymphocytic leukemia (CLL)

This Alliance trial looks at how well ibrutinib and obinutuzumab with or without venetoclax works in treating older patients with previously untreated chronic lymphocytic leukemia (CLL). The drug ibrutinib stops the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induces changes in body's immune system and interfere with the ability of cancer cells to grow and spread. Venetoclax works to stop cancer cells by turning back on programmed cell death. Giving ibrutinib and obinutuzumab with venetoclax may work better at treating CLL than ibrutinib alone.

Study Rationale
The recently completed Alliance trial A041202 established ibrutinib as a frontline treatlment for CLL [1]. While ibrutinib is hghly effective in previously untreated patients with CLL, there do remain disadvantage to this therapy. Specifically, the low rate of complete response (CR) and need for continuous administration. Currently, a number of studies have been designed with the goal of discontinuing ibrutinib therapy by administering combinations with either chemotherapy or additional targeted therapies. However, no studies have been undertaken to this point to randomize patients to continue versus discontinue ibrutinib. Alliance A041702 has the potential to diminish toxicity of the drug as well as drug costs significantly for patients who attain bone marrow (BM) minimal residue disease (MRD) status and can go off therapy. 

Venetoclax has demonstrated considerable efficacy in CLL, both alone and in combination with ibrutinib or monoclonal antibody therapy. It has been well tolerated across studies, and is a rational drug to combine with ibrutinib given preclinical data suggesting synergy, as well as extraordinary clinical results as a single agent including impressive CR rates even in the relapsed population [2-3]. The combination of ibrutinib with venetoclax and obinutuzumab is currently under investigation in the phase I/II setting in both treatment-naïve and relapsed/refractory CLL. Based on previous trials showing a survival advantage for initial therapy even in the setting of active agents for second line therapy, Alliance investigators find that investigation of a combination of these most active agents in the up-front setting is justified [4-5]. As a secondary endpoint, this trial will collect overall survival (OS) data.

Study Outcomes
The primary and secondary objectives are described below.

Primary objective:
To compare the progression-free survival (PFS) between control treatment and experimental treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.

Secondary objectives:
1. To compare BM MRD complete response (CR) rates and depth of response at cycle 15 day 1 between patients treated with IO versus IVO.
2. To compare OS between the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.
3. To compare the 5-year PFS and OS for the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.
4. To describe the toxicity profile for each of the treatment strategies and by each treatment course.

Key Eligibility Criteria
Some of the eligibility criteria include:

Inclusion Criteria:
Pre-Registration Eligibility Criteria (Step 0)

·      Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease

·      Blood submission is mandatory prior to registration/randomization to perform fluorescence in situ hybridization (FISH) centrally that will be used for stratification. It should be obtained as soon after pre-registration as possible

Registration Eligibility Criteria (Step 1)

·      Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria

·      Patients must be intermediate or high-risk Rai stage CLL

·      Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines

·      Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)

·      Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least four weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration

·      Age > 70 years

·      ECOG Performance Status 0-2

Re-Registration Eligibility Criteria (Step 2)

·      Completion of treatment through cycle 14 day 28, and remain on ibrutinib therapy

·      Receipt of central BM MRD results

·      Response assessment completed with CR determination

Description of Treatment
Patients will be randomized into one of two groups. Those in Group 1 will receive ibrutinib orally once daily continuously in 28-day cycles. They will also receive obinutuzumab intravenously for six cycles. Treatment continues indefinitely in the absence of disease progression or unacceptable toxicity. Beginning with course 16, patients receive ibrutinib orally once daily every 28 days in the absence of disease progression or unacceptable toxicity. Those patients in Group 2 will receive ibrutinib orally once daily continuously in 28-day cycles. They also receive obinutuzumab intravenously days for six cycles. Beginning with cycle 3, patients also receive venetoclax orally once daily continuously in 28-day cycles. Treatment continues every 28 days for up to 15 total cycles from the start of therapy. Beginning with cycle 16, patients who do not achieve a BM MRD negative CR, receive ibrutinib orally once daily continuously until disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR discontinue therapy and undergo observation every three cycles for six years, then every six cycles thereafter.

After completion of study treatment, patients will be followed every six months for 10 years from registration.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan and patient eligibility.

Study Chair: Jennifer Woyach, MD - Ohio State University
Activated: 1/04/2019
Status: Now accepting now patients
ClinicalTrials.gov Identifier:

1. Woyach, JA, et al., Ibrutinib Regimens versus Chemoimmunotherapy in Older Patiens with Untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528.
2. Cervantes-Gomez, F., et al., Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.Clin Cancer Res, 2015. 21(16): p. 3705-15.
3. Woodland, R.T., et al., Regulation of B cell survival in xid mice by the proto-oncogene bcl-2.J Immunol, 1996. 156(6): p. 2143-54.
4. Burger, J.A., et al., Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.N Engl J Med, 2015. 373(25): p. 2425-37.
5. Goede, V., et al., Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.N Engl J Med, 2014. 370(12): p. 1101-10.



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