E-Newsletter - March 2019
Spotlight on Alliance Trials


Alliance Trial to seek Better Prognosis for Patients with Acute Lymphoblastic Leukemia

Alliance A041703 - A phase II study of inotuzumab ozogamicin followed by blinatumomab for Ph-negative CD22-positive B-lineage acute lymphoblastic leukemia in newly diagnosed older adults or adults with relapsed or refractory disease

This Alliance trial looks to determine whether investigators can improve the chance of a patient’s leukemia remission and lower the chance of it relapsing by combining two drugs (inotuzumab ozogamicin and blinatumomab) for acute lymphoblastic leukemia. More specifically, this trial will study how well inotuzumab ozogamicin and blinatumomab work in treating patients with CD22-positive B-lineage acute lymphoblastic leukemia that is newly diagnosed, has come back, or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread.

Note that participation on this trial’s initial tolerability portion is limited to specific Alliance institutions. Once tolerability is confirmed, the trial will be open to all National Cancer Institute National Clinical Trials Network (NCTN) sites.

Study Rationale
Nearly 6,000 people in the U.S. are diagnosed with acute lymphoblastic leukemia (ALL) each year and about half of the cases occur in people over the age of 18. Although long-term survival has dramatically improved in pediatric ALL over the last 30 years with cure in about 80 percent of cases, adults with ALL have a much poorer prognosis. Data for patients over the age of 65 to 70 is minimal as most trials have either excluded or failed to enroll significant numbers of patients in this age group.

Progress in the treatment of patients over the age of 60 with ALL will require reducing treatment-related toxicity while improving the efficacy of induction and post-remission therapy. Until recently, active agents with more favorable toxicity profiles were not available but newer targeted agents and immunotherapies hold promise to improve outcomes for this at-need population. Recently developed therapies such as blinatumomab, inotuzumab  ozogamicin, and anti-CD19 chimeric antigen receptor T-cells have promising response rates in a desperate population although duration of response is typically short.

Given the failure of traditional multi-agent chemotherapy in untreated Ph-negative B-cell ALL in older, transplant-ineligible patients, investigations into novel targeted agents as front-line therapy is warranted to reduce toxicity and improve long-term survival in this population. The use of inotuzumab ozogamicin followed by blinatumomab may have multiple beneficial effects in untreated older B-lineage ALL. Based on its excellent safety and toxicity profile in the relapsed setting, induction with inotuzumab ozogamicin is predicted to be safer and more tolerable than multi-agent chemotherapy in this population predicting lower induction mortality.

Inotuzumab ozogamicin yields high CR/CRi rates in relapsed/refractory CD22-positive B-cell ALL but with short duration of response. Blinatumomab can yield prolonged remissions but is most effective in the presence of low burden disease at initiation of therapy. In addition, improving outcomes with T-cell-dependent therapies such as blinatumomab may be difficult as combinations with traditional lymphotoxic therapies might reduce or eliminate the effectiveness of the drug. The combination of inotuzumab ozogamicin followed by blinatumomab is predicted to increase response rates, increase remission durations, be safe and tolerable, and help bridge more patients to allogeneic hematopoietic cell transplantation (HCT).

Study Outcomes
The primary and secondary objectives are described below.

Primary objectives:

1.    Confirmation of Tolerability: To confirm tolerability of the combination regimen of inotuzumab ozogamicin followed by blinatumomab.

2.    Cohort 1: To estimate the 1-year event-free survival of older, transplant-ineligible patients with newly diagnosed, Ph-negative, CD22-positive B-cell ALL treated with inotuzumab ozogamicin induction followed by blinatumomab consolidation.

3.    Cohort 2: To estimate the 1-year event-free survival of patients with relapsed or refractory Ph-negative, CD22-positive B-cell ALL treated with inotuzumab ozogamicin induction followed by blinatumomab consolidation.

Secondary objectives:

Cohort 1: Untreated Ph-negative, CD22-positive B-cell ALL in transplant-ineligible older patients

1.    To estimate the median, 1-year, and 3-year overall survival(OS) in all eligible patients.

2.    To estimate the median, 1-year, and 3-year relapse-free survival(RFS) in all eligible patients.

3.    To estimate the median and 3-year event-free survival (EFS) in all eligible patients.

4.    To estimate the CR rate and overall response rate (ORR, defined as complete response[CR]+ complete response with incomplete count recovery[CRi]) to inotuzumab ozogamicin followed by blinatumomab (regimen CR rate and ORR).

5.    To estimate the CR rate and ORR (CR + CRi) to inotuzumab ozogamicin induction alone (induction CR and ORR).

6.    To estimate the minimal residual disease (MRD) negativity rate in subjects achieving a CR or CRi.

7.    To estimate the treatment-related mortality with this regimen.

8.    To describe the safety and tolerability of this regimen.

Cohort 2: Relapsed or refractory Ph-negative, CD22-positive, B-cell ALL patients

1.    To estimate the median, 1-year, and 3-year OS in all eligible patients.

2.    To estimate the median, 1-year, and 3-year RFS in all eligible patients.

3.    To estimate the median and 3-year EFS in all eligible patients.

4.    To estimate ORR (CR/CRi and CR/complete response with partial hematologic recovery [CRh]) to blinatumomab in patients with ALL refractory to inotuzumab ozogamicin.

5.    To estimate the CR, CRi, and CRh rates at defined time points and cumulatively for the entire regimen.

6.    To determine the MRD negativity (< 10-4) rate at defined time points including prior to allogeneic HCT and cumulatively in patients achieving a CR, CRh, or CRi.

7.    To determine the allogeneic HCT rate in eligible subjects.

8.    To estimate the treatment-related mortality with this regimen.

9.    To describe the safety and tolerability of this regimen.

Key Eligibility Criteria
Some of the eligibility criteria include:

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

·      Submission of bone marrow aspirate and peripheral blood for MRD analysis is mandatory prior to registration; the bone marrow sample should be from the first aspiration (i.e., first pull). It should be initiated as soon as possible after pre-registration. The specimens should be sent to the HEME Biobank.

o   Lumbar Puncture (Spinal Tap) and Intrathecal Methotrexate

Registration Eligibility Criteria (Step 1)

·      Morphologic diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) based on World Health Organization (WHO) criteria. Patients with Burkitt lymphoma/leukemia are not eligible.

·      CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts by local hematopathology evaluation.

·      Philadelphia chromosome/BCR-ABL1-negative ALL by cytogenetics, fluorescence in situ hybridization (FISH), and/or polymerase chain reaction (PCR). If any test is positive for Philadelphia chromosome/BCR-ABL1, then the patient is ineligible.

·      No active central nervous system (CNS) leukemia (i.e., only CNS-1 disease allowed).

·      Patients with known or suspected testicular involvement by leukemia are allowed provided that the patient receives concomitant scrotal/testicular radiotherapy.

·      Not pregnant and not nursing.

·      ECOG Performance Status 0-2

Cohort 1 Patients Only

·      Age > 60 years

·      No prior treatment for ALL except a single dose of intrathecal chemotherapy, corticosteroids, hydroxyurea, and/or leukapheresis to reduce peripheral blast count and prevent ALL complications.

·      No plan for allogeneic or autologous hematopoietic cell transplantation (HCT).

    Cohort 2 Patients Only

·      Age > 18 years

·      Relapsed or refractory disease in salvage 1 or 2.

·      No isolated extramedullary relapse.

·      Prior allogeneic HCT permitted.

·      Patients with prior allogeneic HCT must have completed transplantation > 4 months prior to registration.

·      Patients with prior allogeneic HCT must have no evidence of graft-versus-host disease and must have completed immunosuppressive therapy > 30 days prior to registration.

·      Prior treatment with inotuzumab ozogamicin, blinatumomab, other CD22-directed therapy, or other CD19-directed therapy is not allowed.

Description of Treatment
There will be a limited-access confirmation of tolerability portion prior to the phase II study. While inotuzumab ozogamicin and blinatumomab will be given following each other (sequentially), there is still a possibility of unforeseen toxicities with these drugs given this way. As a result, six patients will be enrolled to either cohort before enrollment of the entire study to assess safety and tolerability. Patients in the confirmation of tolerability portion of the study will get the same treatment as other patients in the phase II portion.

Patients will be assigned to one of two groups (cohorts) based on their diagnosis. Cohort 1 will include patients 60 years and older with newly diagnosed B-lineage ALL. Cohort 2 will include patients 18 years and older with relapsed or refractory B-lineage ALL. Both Cohort 1 and Cohort 2 will undergo the same induction therapy with either one or two courses of inotuzumab ozogamicin for 21 days. A bone marrow aspirate, bone marrow biopsy, and a peripheral blood sample taken between the 18th and 21st day to assess induction response and minimal residual disease status. This will determine whether a patient will receive additional courses of induction therapy with inotuzumab ozogamicin or whether a patient will move on to consolidation therapy with blinatumomab. Both Cohort 1 and Cohort 2 will receive an 84-day course of consolidation therapy with blinatumomab. A bone marrow aspirate, bone marrow biopsy, and a peripheral blood sample taken between the 39th and 42nd and 81st and 84th day to assess consolidation response and minimal residual disease status. For Cohort 1, based on these results, a patient will receive another 84- or 126-day course of consolidation with blinatumomab or go off treatment into follow-up. For Cohort 2, based on results, a patient will receive either a 126-day course of consolidation with blinatumomab or go off treatment into follow-up.

After treatment, patients from both cohorts will continue with follow-up every three months for three years. After that, patient follow-up will occur every six months for seven more years for a total of 10 years after starting study treatment. In addition, investigators will collect the results of any of the usual blood or bone marrow tests patients have done in the subsequent five years to see if their DNA has changed.

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: Matthew Wieduwilt, MD, PhD - University of California San Diego
E-mail: mwieduwilt@ucsd.edu
Activated: 11/16/2018
Status: Now Accepting New Patients
ClinicalTrials.gov Identifier: NCT03739814

 

For other articles in this issue of the Alliance E-News newsletter, see below.