Avo In R/R And Previously Untreated MCL

NCT04855695 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 21-040
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 3

Brief Summary

This research study is evaluating the combination of three drugs - acalabrutinib, venetoclax, and obinutuzumab - as a possible treatment for relapsed or refractory and untreated mantle cell lymphoma (MCL). The names of the study drugs involved in this study are:

• Acalabrutinib
• Venetoclax
• Obinutuzumab

Conditions

Mantle Cell Lymphoma; Refractory Lymphoma

Keywords

Mantle Cell Lymphoma; Refractory Lymphoma

Outcome Measures

Primary Outcomes (3)

• Recommended Phase 2 Dose for acalabrutinib

  The RP2D will be defined as the highest dose level for which there are no more than 1/6 DLTs observed.

  5 months

• Complete Remission Rate

  Complete remission (CR) rate after 7 cycles of treatment with AVO in treatment naïve (TN) transplant ineligible MCL and TN transplant-eligible, TP53 mutated MCL, cohort B. CR rate after 7 cycles of treatment with AVO in TN TP53-mutated MCL, expansion cohort D. Complete remission (CR) is defined radiographically using 2014 Lugano criteria and a negative bone marrow biopsy by histology, immunohistochemistry, and flow cytometry, if bone marrow was initially involved by MCL at screening. CR, a primary endpoint measured after 7 cycles of AVO, does not incorporate minimal residual disease (MRD) testing

  7 Months

• MRD negative complete remission rate

  Minimal residual disease (MRD) negative (\<1 in 106 cells) CR rate after 7 cycles of treatment with AVO in TN transplant-eligible, TP53 wild type MCL, cohort C

  7 months

Secondary Outcomes (17)

• CR rate after 7 cycles of treatment with AVO in participants with TN TP53-mutated MCL in cohort B and expansion cohort D

  7 cycles

• Complete Remission (CR) rate after 7 cycles in the entire study population

  7 months

• CR rate after 7 cycles cohort A and C

  7 Months

• Partial Response (PR) Rate after 7 cycles

  7 months

• Stable Disease Rate after 7 cycles

  7 months

Study Arms (1)

Acalabrutinib, Venetoclax, and Obinutuzumab

EXPERIMENTAL

The study will consist of 4 parts (Parts A, B, C, and D). In the relapsed/refractory (R/R) MCL setting (Part A), the phase 1 portion consists of a dose finding stage to determine the recommended phase 2 dose (RP2D). It will follow a 3+3 dose finding schema with a minimum of 6 participants. 11 participants will be enrolled in the Part A expansion cohort. Part B will enroll 24 participants with untreated mantle cell lymphoma who are transplant ineligible and/or TP53 mutated. Part C will enroll 12 participants with untreated mantle cell lymphoma who are transplant eligible and TP53 wild type. Part D will enroll 16 participants with untreated mantle cell lymphoma with a TP53 mutation determined by next generation sequencing, regardless of transplant eligibility. Each study drug is given according to a different schedule. Each treatment cycle lasts 28 days (4 weeks). * Acalabrutinib: * Obinutuzumab: * Venetoclax:

Drug: Acalabrutinib; Drug: Venetoclax; Drug: Obinutuzumab

Interventions

Venetoclax DRUG

Venetoclax: oral. daily, dosage per protocol, start cycle 3 and beyond according to schedule outlined in protocol

Also known as: Venclexta

Acalabrutinib, Venetoclax, and Obinutuzumab

Obinutuzumab DRUG

Obinutuzumab: intravenous infusion, dosage per protocol, drug during cycles 2 and beyond according to schedule outlined in protocol

Also known as: Gazyva

Acalabrutinib, Venetoclax, and Obinutuzumab

Acalabrutinib DRUG

Each study drug is given according to a different schedule: Acalabrutinib: Oral, dosage per protocol, start cycle 1 and beyond according to schedule outlined in protocol

Also known as: Calquence, Acalabrutinib maleate

Acalabrutinib, Venetoclax, and Obinutuzumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet the following criteria on screening examination to be eligible to participate in the study:
• Participants must have histologically determined mantle cell lymphoma with pathologic review at the participating institutions, that has either:
• Relapsed or primary refractory after at least one line of therapy including anti-CD20 monoclonal antibody treatment (part A) or; Had no previous anti-lymphoma therapy other than corticosteroids or radiotherapy (parts B, C, and D).
• Participants in part A, relapsed or refractory following prior therapy, may have had a prior autologous or allogeneic stem cell transplant and may have been treated with chimeric antigen receptor T-cells (CAR T-cells).
• Participants in parts B, C, and D, without prior anti-lymphoma therapy, must require treatment as defined by any of the following criteria:
• Symptomatic adenopathy or splenomegaly
• Local symptoms due to extranodal disease
• Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC \<1.5x109/L; absolute neutrophil count \[ANC\] \<1.0x109/L, Hgb \<10g/dL; platelets \<100x109/L)
• Presence of systemic B symptoms (fever, drenching night sweats, or unintentional weight loss ≥ 10% body weight over previous 6 months) or functionally significant fatigue
• Participants in part B without prior anti-lymphoma therapy should be deemed to be ineligible for autologous stem cell transplant by the treating physician and/or have a TP53 mutation detected by next generation sequencing at a variant (mutant) allele fraction above the validated threshold for calling a new variant or high TP53 expression on immunohistochemistry (\>50% positive lymphoma cells)
• Participants in part C without prior anti-lymphoma therapy should be deemed to be eligible for autologous stem cell transplant by the treatment physician and have no evidence of TP53 mutation (TP53 wild type) detected by next generation sequencing and no evidence of high TP53 expression on immunohistochemisty
• Participants in part D without prior anti-lymphoma therapy must have a TP53 mutationdetected by next generation sequencing at a variant (mutant) allele fraction above thevalidated threshold for calling a new variant
• Participants in parts B, C, and D must have an archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy and peripheral blood available for submission to Adaptive Biotechnologies for ClonoSEQ®ID molecular marker identification of a unique clonal immunoglobulin DNA sequence. Only those participants in parts B and C who have a molecular marker identified from the peripheral blood will be eligible for minimal residual disease (MRD) driven treatment interruptions.
• Participants in parts B, C, and D who do not have a molecular marker identified by ClonoSEQ from the peripheral blood will be deemed to be MRD indeterminate and are not eligible for peripheral blood MRD driven treatment interruptions. These participants will be able to enroll in the study assuming all other eligibility criteria are met but will receive 7 cycles of AVO combination therapy followed by 17 cycles of acalabrutinib and venetoclax therapy (24 total cycles of AV) and 2 years of maintenance obinutuzumab for a total of 31 cycles of therapy.
• Measurable disease with a lymph node or tumor mass ≥ 1.5 cm in at least one dimension by CT, PET/CT, or MRI. Patients without measurable disease will be eligible if they have marrow involvement and cytopenias related to their lymphoma (hemoglobin \<10 g/dL, absolute neutrophil count \< 1.0 x 109/L, or platelets \< 100 x 109/L) OR symptomatic splenomegaly \> 15cm in craniocaudal diameter.

You may not qualify if:

• Participants who exhibit any of the following conditions at screening will not eligible for admission into the study:
• Participants who have progressed or relapsed after receiving either a BTK inhibitor or BCL2 inhibitor.
• Participants who are receiving any other investigational agents, or have received investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of beginning treatment.
• Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., within 28 days of the first dose of study drug or chronic administration of \>20 mg/day of prednisone equivalent corticosteroid within 7 days of the first dose)
• \-- Note: Glucocorticoids for lymphoma symptom palliation are allowed but must be discontinued at time of initiation of protocol therapy.
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients with reactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not excluded if they were able to eventually tolerate treatment in an outpatient setting without grade 2 or higher infusion reactions.
• Participants who have a history of other malignancies except:
• Malignancy treated with curative intent and with no known active disease present and felt to be at low risk for recurrence by treating physician. Current adjuvant hormonal therapy for disease treated with curative intent is permissible.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without evidence of disease.
• Low-risk prostate cancer on active surveillance
• Other exceptions may be made after consultation with the study chair
• Participants with known leptomeningeal or brain metastases. Imaging or spinal fluid analysis to exclude CNS involvement is not required, unless there is clinical suspicion by the treating investigator.
• Participants who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, participants who have not adequately recovered from the side effects of any major surgery (defined as requiring general anesthesia), or participants that may require major surgery during the course of the study.
• Vaccinated with live, attenuated vaccines within 28 days of study entry or need for live virus vaccines at any time during study period.

Sponsors & Collaborators

• Roche-Genentech: collaborator
• AstraZeneca: collaborator
• Austin I Kim: lead

Study Sites (3)

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Lymphoma, Mantle-Cell; Lymphoma

Interventions

acalabrutinib; venetoclax; obinutuzumab

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Austin I Kim, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Austin I Kim, MD

CONTACT

(617) 632-6844; AustinI_Kim@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: April 11, 2021
• First Posted: April 22, 2021
• Study Start: July 2, 2021
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: January 21, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (3)