AVO for Mantle Cell Lymphoma

Recruiting at 2 trial locations

Overseen By Austin I Kim, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Austin I Kim

Must not be taking: Investigational agents, Strong CYP3A inhibitors

Disqualifiers: HIV, Active hepatitis, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 7 months

53 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of three drugs—acalabrutinib, venetoclax, and obinutuzumab—to treat mantle cell lymphoma (MCL), a type of non-Hodgkin's lymphoma that can be difficult to treat, especially if it returns or doesn't respond to previous treatments. The study aims to evaluate the effectiveness of these drugs when used together for individuals whose cancer has returned or for those who haven't received any treatment yet. Suitable candidates for this trial have been diagnosed with mantle cell lymphoma and either haven't responded to previous treatments or require treatment due to symptoms like swollen lymph nodes or significant fatigue.

As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group. Participants have the opportunity to contribute to groundbreaking advancements in MCL treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take certain medications like strong CYP3A inhibitors/inducers or P-gp inhibitors during the study. If you are on these, a 7-day period without them is required before starting the trial drugs.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of acalabrutinib, venetoclax, and obinutuzumab is under testing for safety in treating mantle cell lymphoma (MCL).

Acalabrutinib has been used in MCL patients, with studies indicating common side effects like anemia and infections in over 30% of patients. These side effects are usually manageable.

Obinutuzumab can cause reactions during infusions and low white blood cell counts in some patients. More serious side effects, such as neutropenia and pneumonia, are generally manageable with medical care.

Venetoclax has been tested in different types of lymphoma, including MCL. Some patients experience side effects like nausea or diarrhea, but the treatment shows promise in targeting cancer cells.

Each drug's safety has been studied individually. Combining them aims to improve treatment while closely monitoring side effects. Clinical trial participants are carefully observed to manage any adverse effects that might occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Acalabrutinib, Obinutuzumab, and Venetoclax for Mantle Cell Lymphoma because it targets the disease in a novel way. Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor that disrupts cancer cell growth signals, while Venetoclax targets and blocks the BCL-2 protein, which helps cancer cells survive. Obinutuzumab, an anti-CD20 monoclonal antibody, enhances the immune system's ability to destroy cancer cells. Together, these treatments offer a multi-faceted attack on the disease, potentially improving outcomes for patients who have not responded to standard chemotherapy or are ineligible for stem cell transplants.

What evidence suggests that this trial's treatments could be effective for mantle cell lymphoma?

This trial will evaluate the combination of acalabrutinib, venetoclax, and obinutuzumab for treating mantle cell lymphoma (MCL). Research has shown that this drug combination is promising, as studies have found it can significantly reduce the risk of disease progression or death. Patients are less likely to experience cancer progression compared to other treatments. The combination also exhibits strong anti-cancer effects, effectively attacking and fighting cancer cells. Additionally, most patients can tolerate the treatment's side effects. Overall, early evidence suggests that this treatment could be a powerful option for those with MCL. ^{6 7 8 9 10}

Who Is on the Research Team?

Austin Kim, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with mantle cell lymphoma (MCL) that's come back or didn't respond to treatment, and those who haven't been treated yet. Participants need good organ function, agree to use contraception, and provide bone marrow samples. It's not for those who've had certain prior treatments like BTK inhibitors or have conditions like brain metastases or severe infections.

Inclusion Criteria

My lymphoma has been confirmed as mantle cell type by a lab test.

My organs and bone marrow are working well.

I agree to use birth control or abstain from sex for safety after my treatment.

Exclusion Criteria

I haven't had major surgery or significant injury in the last 4 weeks and don't need any during the study.

Significant co-morbid condition or disease which in the judgment of the Principal Investigator would place the participant at undue risk or interfere with the study

I need medication for stomach acid.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of acalabrutinib, venetoclax, and obinutuzumab. Each treatment cycle lasts 28 days (4 weeks).

7 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The study tests a combination of three drugs: Acalabrutinib, Venetoclax, and Obinutuzumab in treating MCL. The goal is to see how well these drugs work together in patients who have relapsed/refractory MCL or are untreated.

How Is the Trial Designed?

Group I: Acalabrutinib, Venetoclax, and Obinutuzumab Experimental Treatment 3 Interventions

This study will consist of 3 parts (Parts A, B, and C). 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 safety pause and evaluation after the first 3 participants have completed through cycle 5, day 1. If there are no dose limiting toxicities (DLTs), an additional 3 participants will be treated and if there are 0 or 1 DLTs seen, the RP2D will have been determined.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. Each study drug is given according to a different schedule. Each treatment cycle lasts 28 days (4 weeks). * Acalabrutinib: * Obinutuzumab: * Venetoclax:

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Austin I Kim

Lead Sponsor

Trials

1

Recruited

50+

Roche-Genentech

Industry Sponsor

Trials

27

Recruited

3,800+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a phase I trial involving 106 patients with various subtypes of non-Hodgkin lymphoma, venetoclax, a BCL-2 inhibitor, was found to be generally well tolerated, with a 44% overall response rate across different lymphoma types.

The study identified 1,200 mg as the recommended dose for future studies in follicular lymphoma and diffuse large B-cell lymphoma, while 800 mg was effective for mantle cell lymphoma, indicating varying efficacy based on lymphoma subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. Davids, MS., Roberts, AW., Seymour, JF., et al.[2018]

Patients with recurrent ovarian cancer are categorized as either platinum-sensitive or platinum-resistant, which influences treatment options; platinum-sensitive patients often benefit from re-treatment with paclitaxel/platinum combinations, while platinum-resistant patients may receive single-agent therapies like altretamine or topotecan.

For platinum-sensitive patients with minimal residual disease, intensive intraperitoneal therapy with cisplatin and paclitaxel shows the most promise for long-term disease-free survival, highlighting the importance of tailored treatment strategies based on disease characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of refractory and recurrent ovarian cancer. Alberts, DS.[2005]

In a phase III trial involving 156 patients with platinum-resistant ovarian carcinoma, adding pertuzumab to chemotherapy did not significantly improve progression-free survival (PFS) compared to placebo, with median PFS of 4.3 months for the pertuzumab group versus 2.6 months for the placebo group.

Subgroup analyses indicated that the addition of pertuzumab showed more promising trends in PFS specifically for patients receiving gemcitabine and paclitaxel, suggesting potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-Blind, Placebo-Controlled, Randomized Phase III Trial Evaluating Pertuzumab Combined With Chemotherapy for Low Tumor Human Epidermal Growth Factor Receptor 3 mRNA-Expressing Platinum-Resistant Ovarian Cancer (PENELOPE). Kurzeder, C., Bover, I., Marmé, F., et al.[2022]

The study involving 42 patients with ovarian cancer demonstrated that the anti-idiotypic monoclonal antibody abagovomab is well tolerated, with common side effects being mild and self-limited, such as injection site pain and myalgia.

Abagovomab successfully induced strong immune responses (Ab3) in all patients, suggesting its potential effectiveness, and a phase III study is recommended to further evaluate its efficacy at the 2.0 mg subcutaneous dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Sabbatini, P., Dupont, J., Aghajanian, C., et al.[2008]

The JAVELIN Ovarian 200 trial is the first Phase III study to investigate the effectiveness of avelumab, a PD-L1 checkpoint inhibitor, in treating women with platinum-resistant ovarian cancer, involving multiple treatment arms to assess its efficacy.

The trial will measure overall survival and progression-free survival as primary outcomes, providing valuable insights into the potential benefits of avelumab alone or in combination with doxorubicin compared to doxorubicin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. Pujade-Lauraine, E., Fujiwara, K., Dychter, SS., et al.[2022]

In a study of 49 patients with advanced epithelial ovarian cancer receiving adjuvant intraperitoneal carboplatin and intravenous dose-dense paclitaxel, the treatment was well-tolerated, with 87.8% completing six cycles of chemotherapy.

The side effects observed, such as neutropenia (32.7%) and the need for red blood cell transfusions (28.6%), were comparable to or better than those reported in traditional treatment regimens, indicating a favorable safety profile for this chemotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer. Bisch, SP., Sugimoto, A., Prefontaine, M., et al.[2019]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

In a retrospective study of 34 adult patients with various types of non-Hodgkin lymphoma treated off-label with venetoclax, the overall response rate was 26%, indicating modest efficacy in heavily pretreated patients.

Adverse events occurred in 76% of patients, with higher incidence than reported in clinical trials, highlighting the need for further investigation into the safety and dosing strategies of venetoclax in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. Hughes, ME., Landsburg, DJ., Rubin, DJ., et al.[2020]

In a study of 24 patients with relapsed mantle cell lymphoma (MCL) who had undergone multiple prior therapies, venetoclax treatment resulted in a 50% overall response rate and a 21% complete response rate, with a median follow-up of 17 months.

Genomic analysis revealed that resistance to venetoclax is linked to mutations in non-BCL2 genes, with specific alterations like SMARCA4 and KMT2C/D emerging after treatment progression, indicating a need for further research into combination therapies and the mechanisms of resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. Zhao, S., Kanagal-Shamanna, R., Navsaria, L., et al.[2020]

The combination of venetoclax (VEN) and ibrutinib (IBR) showed a high overall response rate of 93.8% at the optimal dosing of VEN 200 mg and IBR 420 mg in treating relapsed mantle cell lymphoma (MCL) among 35 participants.

The study found that higher doses of VEN and IBR did not improve efficacy and were associated with increased toxicity, highlighting the importance of dose optimization in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Portell, CA., Wages, NA., Kahl, BS., et al.[2022]

Venetoclax, a BCL2-targeting drug, shows promising anticancer activity in mantle cell lymphoma (MCL), but resistance mechanisms involving proapoptotic proteins BIM and NOXA complicate its effectiveness.

Combining venetoclax with the MCL1 inhibitor S63845 resulted in synthetic lethality in patient-derived xenografts of relapsed MCL, suggesting this combination could be a novel treatment strategy for patients with chemoresistant MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. Prukova, D., Andera, L., Nahacka, Z., et al.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Citations

1. astrazeneca.com astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration Calquence plus venetoclax demonstrated ... Calquence plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11399641/

Acalabrutinib plus venetoclax and rituximab in treatment-naive ... Acalabrutinib plus venetoclax and rituximab resulted in high clinical and molecular response rates in patients with TN MCL. This chemotherapy-free, targeted ...

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/fixed-duration-calquence-acalabrutinib-plus-venetoclax-with-or-without-obinutuzumab-significantly-improved-progression-free-survival-in-first-line-chronic-lymphocytic-leukemia-in-amplify-phase-iii-trial.html

Fixed-duration CALQUENCE® (acalabrutinib) plus ... Fixed-duration CALQUENCE® (acalabrutinib) plus venetoclax, with or without obinutuzumab, significantly improved progression-free survival in 1st ...

4. onclive.com onclive.com/view/acalabrutinib-plus-venetoclax-obinutuzumab-demonstrates-efficacy-safety-in-mantle-cell-lymphoma

Acalabrutinib Plus Venetoclax/Obinutuzumab ... Acalabrutinib plus venetoclax and obinutuzumab demonstrated antitumor activity with a manageable safety profile in mantle cell lymphoma.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05211856

NCT05211856 | Study of Acalabrutinib (ACP-196) in ... This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR)

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/210259s011lbl.pdf

Reference ID: 5512932 - accessdata.fda.gov The safety data described below reflect exposure to CALQUENCE (100 mg approximately every. 12 hours, with or without BR) in patients with MCL [see Clinical ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/216387Orig2s000Correctedlbl.pdf

CALQUENCE® (acalabrutinib) tablets, for oral use In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7744/528340/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... Real-world effectiveness and safety outcomes of Acalabrutinib treatment in patients with relapsed/refractory mantle cell lymphoma.

9. calquencehcp.com calquencehcp.com/mcl.html

The first and only BTKi approved in 1L MCL - Calquence Safety Data ... CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT02213926

NCT02213926 | An Open-label, Phase 2 Study of ACP-196 ... The purpose of this study is to characterize the safety and efficacy profile of ACP-196 (acalabrutinib) in subjects with relapsed or refractory Mantle Cell ...