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

Trial Summary

What is the purpose of this trial?

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

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Obinutuzumab, and Venetoclax for treating Mantle Cell Lymphoma?

Research shows that a similar combination of drugs, including Obinutuzumab and Venetoclax, has been effective in treating Mantle Cell Lymphoma, with high response rates and good tolerance in patients. In one study, 67% of relapsed patients and 86.6% of untreated patients achieved complete response, indicating the potential effectiveness of this drug combination. ^{1 2 3 4 5}

Is the AVO treatment safe for humans?

Venetoclax, a component of the AVO treatment, has been generally well tolerated in clinical trials for various types of lymphoma, including mantle cell lymphoma. Common side effects include low blood cell counts, but these can often be managed with dose adjustments and supportive care. No severe safety concerns have been consistently reported across studies. ^{4 5 6 7 8}

What makes the AVO drug combination unique for treating Mantle Cell Lymphoma?

The AVO drug combination for Mantle Cell Lymphoma is unique because it combines three targeted therapies: Acalabrutinib, Obinutuzumab, and Venetoclax, which work together to block cancer cell growth and survival pathways, offering a novel approach compared to traditional chemotherapy. ^{9 10 11 12 13}

Research Team

Austin Kim, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. [2018]

5. United States 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. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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

7. United States pubmed.ncbi.nlm.nih.gov

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Treatment of refractory and recurrent ovarian cancer. [2005]

10. United States pubmed.ncbi.nlm.nih.gov

Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. [2008]

11. United States 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). [2022]

12. England pubmed.ncbi.nlm.nih.gov

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer. [2019]