Glofitamab Combinations for Richter's Transformation

Recruiting at 3 trial locations

Overseen By Matthew S. Davids

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Christine Ryan

Must not be taking: Anti-CD20 antibodies, CAR T-cell

Disqualifiers: Hodgkin variant, CNS disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 25

Duration: 9 months

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This research is being done to evaluate Glofitamab by itself or in combination with Polatuzumab Vedotin, Pirtobrutinib, or Atezolizumab as possible treatments for Chronic Lymphocytic Leukemia (CLL) that has transformed into Richter's Transformation (RT). The names of the study drugs involved in this research study are: * Glofitamab (a T-cell bispecific humanized monoclonal antibody) * Obinutuzumab (a humanized glycoengineered type II anti-CD20 monoclonal antibody) * Polatuzumab vedotin (an antibody-drug conjugate) * Pirtobrutinib (a selective inhibitor of BTK) * Atezolizumab (a humanized immunoglobulin monoclonal antibody) * Tocilizumab (a recombinant, humanized, anti-human monoclonal antibody)

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have received certain treatments like targeted therapies or immunotherapy within 14 days before starting the trial. You may continue taking a Bruton's tyrosine kinase inhibitor until the day before starting the trial to avoid tumor flare.

What data supports the effectiveness of the drug combination for treating Richter's Transformation?

Recent studies suggest that novel targeted therapies, like T-cell-engaging bispecific antibodies and conjugated monoclonal antibodies, show promise in improving outcomes for Richter's Transformation, especially when used in combination with other treatments. ^{1 2 3 4 5}

Is tocilizumab safe for human use?

Tocilizumab has been studied in various conditions like rheumatoid arthritis and giant cell arteritis, and it is generally well tolerated, though infections are the most common side effect. Long-term studies up to 9 years show that it remains effective and generally safe for use in humans. ^{6 7 8 9 10}

What makes the drug combination for Richter's Transformation unique?

This drug combination is unique because it includes a mix of targeted therapies like Glofitamab and Atezolizumab, which are designed to work together to enhance the immune system's ability to fight cancer cells, offering a novel approach compared to traditional chemotherapy. ^{11 12 13 14 15}

Research Team

Christine Ryan, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults over 18 with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma that's turned into a more aggressive form called Richter's Transformation. They should have certain normal organ and blood cell levels, no severe recent treatments, and be willing to use effective birth control. Those who've had specific prior therapies or other cancers aren't eligible.

Inclusion Criteria

I have CLL or SLL that has transformed into DLBCL, known as Richter's Transformation.

I had an allogeneic transplant over 6 months ago, no severe GVHD, and have been off immunosuppressants for 2+ months.

My organ and bone marrow functions are within required ranges.

Exclusion Criteria

My condition is not Hodgkin variant transformation of CLL.

I have had cancer before.

I haven't taken any cancer-targeting drugs or immune therapies in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive study treatment with Glofitamab, Obinutuzumab, and either Polatuzumab Vedotin or Atezolizumab for about 9 months

9 months

Regular visits every 21 days for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Every 3 months for months 10-24, then every 6 months for months 25-60

Treatment Details

Interventions

• Atezolizumab
• Glofitamab
• Obinutuzumab
• Polatuzumab Vedotin
• Tocilizumab

Trial Overview Researchers are testing Glofitamab alone or combined with Polatuzumab Vedotin or Atezolizumab as treatments for CLL/RT. These drugs include monoclonal antibodies targeting cancer cells in different ways, aiming to improve the body’s immune response against cancer.

Participant Groups

Group I: Combination C Group: Obinutuzumab, Glofitamab, and Atezolizumab Experimental Treatment 4 Interventions

Study procedures will be conducted as follows: * Baseline visit with screening procedures, including bone marrow biopsy and PET/CT scans. * PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. * Cycle 1: * Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. * Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. * Cycle 2 - 12 - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Predetermined dose of Atezolizumab 1x daily. * End of treatment visit. * Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months.

Group II: Combination B Group: Obinutuzumab, Glofitamab, and Pirtobrutinib Experimental Treatment 4 Interventions

Study procedures will be conducted as follows: * Baseline visit with screening procedures, including bone marrow biopsy and PET/CT scans. * PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. * Cycle 1: * Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. * Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. * Cycle 2 - 12 - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Predetermined dose of Pirtobrutinib 1x daily. Days 2-21 of each cycle: Pirtobrutinib will be taken once daily. * End of treatment visit. * Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months.

Group III: Combination A Group: Obinutuzumab, Glofitamab, and Polatuzumab Vedotin Experimental Treatment 4 Interventions

Study procedures will be conducted as follows: * Baseline visit with screening procedures, including bone marrow biopsy and PET/CT scans. * PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. * Cycle 1: * Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. * Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. * Cycle 2 - 7: - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Predetermined dose of Polatuzumab Vedotin 1x daily. * Cycle 8 - 12 - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. * End of treatment visit. * Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months.

Group IV: Monotherapy Cohort: Obinutuzumab and Glofitamab Active Control 3 Interventions

Study procedures will be conducted as follows: * Baseline visit with screening procedures, including bone marrow biopsy and Positron Emission Tomography (PET) or Computed Topography (CT) scans. * PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. * Cycle 1: * Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. * Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. * Cycle 2 - 12 --Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for second dose and post-dose observation * End of treatment visit. * Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months. * After completion of a 10-patient safety lead-in cohort, enrollment will open to the other two cohorts.

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Christine Ryan

Lead Sponsor

Trials

2

Recruited

130+

Matthew S. Davids, MD

Lead Sponsor

Trials

1

Recruited

70+

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

Loxo Oncology, Inc.

Industry Sponsor

Trials

72

Recruited

11,600+

Jacob Van Naarden

Loxo Oncology, Inc.

Chief Executive Officer since 2019

A.B. in Molecular Biology from Princeton University

Dr. Jennifer Low

Loxo Oncology, Inc.

Chief Medical Officer since 2014

MD and PhD from Georgetown University; Undergraduate degree from California Institute of Technology

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

Richter's transformation (RT) is a serious condition that arises from chronic lymphocytic leukemia, and traditional chemotherapy treatments have had limited success due to the aggressive nature of the disease.

Recent advances in targeted therapies, such as Bruton tyrosine kinase inhibitors and T-cell-engaging bispecific antibodies, show promise for improving treatment outcomes in RT, suggesting that a combination of these novel therapies may be more effective than traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SOHO State of the Art Updates and Next Questions | Treatment of Richter's Transformation. Romano, I., Condoluci, A., Rossi, D.[2023]

In a study of 25 patients with Richter transformation, acalabrutinib showed an overall response rate of 40%, with 8% achieving a complete response and 32% a partial response, indicating some efficacy in this challenging patient population.

While acalabrutinib was generally well tolerated, with manageable side effects, the median progression-free survival was only 3.2 months, suggesting that its effectiveness as a monotherapy is limited and highlighting the need for further research into combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. Eyre, TA., Schuh, A., Wierda, WG., et al.[2022]

This study presents a rare case of chronic lymphocytic leukemia (CLL) transforming into classical Hodgkin lymphoma (cHL), highlighting the aggressive nature of Richter's transformation in CLL.

The common clonal origin of CLL and cHL was confirmed through immunoglobulin gene rearrangement analysis, indicating a shared genetic background, but treatment outcomes for secondary Hodgkin lymphoma are generally poor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hodgkin's lymphoma as a rare variant of Richter's transformation in chronic lymphocytic leukemia: A case report and review of the literature. Janjetovic, S., Bernd, HW., Bokemeyer, C., et al.[2020]

In a phase 2 study involving 59 patients with Richter transformation of chronic lymphocytic leukemia, the combination of the PD-1 inhibitor tislelizumab and the BTK inhibitor zanubrutinib resulted in a significant overall response rate of 58.3%, surpassing the predefined threshold of 40%.

The treatment was well-tolerated, with a 12-month overall survival rate of 74.7%, indicating that this combination therapy is both effective and safe for patients with this aggressive form of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Al-Sawaf, O., Ligtvoet, R., Robrecht, S., et al.[2023]

Richter transformation (RT) is a severe form of lymphoma that arises in patients with chronic lymphocytic leukemia, and it generally has a poor response to standard treatments, highlighting the need for new therapeutic strategies.

Recent advancements in targeted therapies, such as CAR T-cell therapy and Bruton tyrosine kinase inhibitors, show promise for improving outcomes in RT patients, but further large-scale clinical trials are necessary to establish their safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging Therapies for the Management of Richter Transformation. Smyth, E., Eyre, TA., Cheah, CY.[2023]

Tocilizumab is a humanized monoclonal antibody that targets the interleukin-6 receptor, showing efficacy in treating conditions like Castleman disease and various types of arthritis, with approval in Japan and the European Union for these uses.

The drug is currently under review by the US FDA for moderate-to-severe rheumatoid arthritis and has potential applications for other IL-6 related disorders, such as Crohn's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab. Venkiteshwaran, A.[2021]

In the GiACTA trial involving 250 patients with giant cell arteritis (GCA), tocilizumab (TCZ) significantly improved sustained remission rates compared to placebo across all symptom groups: 45.2% for PMR symptoms only, 60.3% for cranial symptoms only, and 55.0% for both symptoms.

Patients treated with TCZ experienced fewer disease flares than those on placebo, with notable reductions in flare rates for those with cranial symptoms and both symptoms, indicating TCZ's efficacy regardless of the specific symptoms presented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab vs placebo for the treatment of giant cell arteritis with polymyalgia rheumatica symptoms, cranial symptoms or both in a randomized trial. Spiera, R., Unizony, SH., Bao, M., et al.[2021]

Tocilizumab, an IL-6 receptor antagonist, is effective and well tolerated for treating moderate to severe rheumatoid arthritis, showing better results than placebo and other DMARDs in reducing disease activity and improving quality of life.

It is particularly beneficial for patients who have not responded to anti-TNF therapies, making it a valuable option for those with long-standing rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab: a review of its use in the management of rheumatoid arthritis. Oldfield, V., Dhillon, S., Plosker, GL.[2021]

Tocilizumab is an effective treatment for adults with moderate to severe rheumatoid arthritis (RA), showing beneficial effects on disease symptoms and quality of life, based on several large clinical trials and studies.

Long-term use of tocilizumab (up to 9 years) is generally well tolerated, with infections being the most common side effect, and it has been shown to be more effective than adalimumab in patients who cannot continue methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. Dhillon, S.[2022]

The GiACTA trial is a large-scale study involving 250 patients across approximately 100 centers, designed to evaluate the effectiveness of tocilizumab (TCZ) in maintaining remission in patients with giant cell arteritis (GCA) over a 52-week period.

The trial aims to determine if TCZ, an IL-6 receptor antagonist, can improve sustained remission rates compared to a standard prednisone taper, potentially reducing the long-term side effects associated with corticosteroid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the tocilizumab in giant cell arteritis trial. Unizony, SH., Dasgupta, B., Fisheleva, E., et al.[2022]

Pemetrexed is a multitargeted antifolate that has demonstrated effectiveness against various solid tumors, including those in the genitourinary tract.

It shows promising results when used in combination with other chemotherapy agents like gemcitabine, suggesting potential for further research in advanced and adjuvant treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief communication: use of the multitargeted antifolate pemetrexed (Alimta) in genitourinary cancer. Misset, JL.[2022]

In a study of 200 patients with untreated advanced gastric carcinoma, the PELF treatment regimen showed a significantly higher complete response rate (13%) compared to the FAMTX regimen (2%), indicating greater efficacy in treating this type of cancer.

The objective response rates were also better for PELF (39%) versus FAMTX (22%), suggesting that PELF is a more effective treatment option, although the survival rate differences were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Cocconi, G., Carlini, P., Gamboni, A., et al.[2022]

Pemetrexed is a multitargeted antifolate that effectively inhibits key enzymes involved in cancer cell growth and is active against various solid tumors, including non-small-cell lung cancer and ovarian cancer.

A recent randomized trial found that administering pemetrexed followed by gemcitabine on specific days every 21 days resulted in the best efficacy and lowest toxicity, highlighting an optimized treatment sequence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical studies of pemetrexed and gemcitabine combinations. Adjei, AA.[2022]

In a study involving 382 patients with untreated advanced colorectal cancer, the addition of trimetrexate (TMTX) to the standard treatment of 5-fluorouracil (5-FU) and leucovorin (LCV) resulted in increased severe diarrhea but did not improve overall survival (OS) or progression-free survival (PFS).

The trial found that while TMTX led to more significant toxicities, including a 41% incidence of grade 3 or 4 diarrhea compared to 28% in the placebo group, it did not enhance treatment efficacy, as response rates and quality of life scores were similar between the TMTX and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Blanke, CD., Shultz, J., Cox, J., et al.[2020]

Pemetrexed disodium is a multitargeted antifolate that works by inhibiting key enzymes involved in DNA synthesis, making it effective against various solid tumors, including breast cancer.

When combined with gemcitabine, pemetrexed disodium shows promising clinical activity for treating metastatic breast cancer, indicating its potential as a combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and Pemetrexed disodium in treating breast cancer. Adjei, AA.[2022]

References

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

SOHO State of the Art Updates and Next Questions | Treatment of Richter's Transformation. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Hodgkin's lymphoma as a rare variant of Richter's transformation in chronic lymphocytic leukemia: A case report and review of the literature. [2020]

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

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. [2023]

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

Emerging Therapies for the Management of Richter Transformation. [2023]

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

Tocilizumab. [2021]

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

Tocilizumab vs placebo for the treatment of giant cell arteritis with polymyalgia rheumatica symptoms, cranial symptoms or both in a randomized trial. [2021]

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

Tocilizumab: a review of its use in the management of rheumatoid arthritis. [2021]

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

Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. [2022]

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

Design of the tocilizumab in giant cell arteritis trial. [2022]

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

Brief communication: use of the multitargeted antifolate pemetrexed (Alimta) in genitourinary cancer. [2022]

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

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Clinical studies of pemetrexed and gemcitabine combinations. [2022]

14. England pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. [2020]

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

Gemcitabine and Pemetrexed disodium in treating breast cancer. [2022]