Combination Chemotherapy for Lymphoma

Overseen By Jason Westin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Aspirin

Must not be taking: Proton pump inhibitors

Disqualifiers: Uncontrolled hypertension, HIV, Hepatitis B, 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: 9

62 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of rituximab, lenalidomide, acalabrutinib, tafasitamab alone and in combination with chemotherapy in treating patients with newly diagnosed non-germinal center diffuse large B-cell lymphoma. Rituximab and tafasitamab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. Acalabrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as lenalidomide, cyclophosphamide, doxorubicin, and vincristine, and work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs, such as prednisone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving rituximab, lenalidomide, acalabrutinib, tafasitamab alone and with combination chemotherapy may help control non-germinal center diffuse large B-cell lymphoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you cannot take certain medications like strong CYP3A inhibitors, warfarin, or proton pump inhibitors during the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination used in the clinical trial for lymphoma?

Research shows that rituximab, when combined with chemotherapy, improves survival and tumor remission in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Additionally, acalabrutinib has been shown to significantly extend the time before disease progression in chronic lymphocytic leukemia. These findings suggest that components of the drug combination may be effective in treating lymphoma. ^{1 2 3 4 5}

Is the combination chemotherapy for lymphoma generally safe in humans?

The safety of doxorubicin, one of the drugs in the combination, has been studied in breast cancer treatments, showing some side effects like hair loss. However, specific safety data for the entire combination used in lymphoma is not provided in the available research. ^{6 7 8 9 10}

What makes the combination chemotherapy for lymphoma unique?

This combination chemotherapy for lymphoma is unique because it includes a mix of drugs like acalabrutinib, lenalidomide, and tafasitamab, which are not typically used together in standard regimens. Acalabrutinib targets specific proteins in cancer cells, lenalidomide modulates the immune system, and tafasitamab is a monoclonal antibody that helps the immune system attack cancer cells, offering a novel approach to treating lymphoma. ^{11 12 13 14 15}

Research Team

Jason Westin

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults diagnosed with non-germinal center diffuse large B-cell lymphoma who haven't had treatment, except possibly a short course of steroids or one dose of cyclophosphamide for urgent issues. They must have measurable disease, acceptable liver and kidney function, no significant neuropathy or serious medical conditions, not be pregnant or breastfeeding, able to sign consent form, willing to follow birth control requirements and join the REMS program.

Inclusion Criteria

I have only had limited radiotherapy, short-term steroids, or a single dose of cyclophosphamide for urgent issues.

I can take daily aspirin or a similar medication for blood thinning.

I am registered and can follow the Revlimid REMS program requirements.

Exclusion Criteria

Pregnant or lactating females

I cannot take certain medications or treatments due to other health issues.

Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment (SMART STOP)

Participants receive rituximab, acalabrutinib, lenalidomide, and tafasitamab for up to 4 cycles

12 weeks

3 visits per cycle (in-person)

Extended Treatment (uLTRA-CHOP)

Participants who achieve a complete response receive additional cycles with CHOP chemotherapy

18 weeks

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months for 1 year, then every 4 months for 1 year

Treatment Details

Interventions

• Acalabrutinib
• Doxorubicin Hydrochloride
• Lenalidomide
• Prednisone
• Rituximab
• Tafasitamab
• Vincristine

Trial Overview The trial is testing rituximab, lenalidomide, acalabrutinib, tafasitamab alone and in combination with chemotherapy drugs (prednisone, doxorubicin hydrochloride, cyclophosphamide, vincristine) for treating newly diagnosed non-germinal center diffuse large B-cell lymphoma. The goal is to see how well these treatments work together in controlling this type of lymphoma.

Participant Groups

Group I: Treatment (uLTRA, CHOP) Experimental Treatment 8 Interventions

COHORT I (SMART STOP): Patients receive rituximab IV over 4-6 hours on day 1, acalabrutinib PO BID on days 1-21, lenalidomide QD on days 1-10, and tafasitamab IV over 2 hours on days 1, 8, and 15. Treatments repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. COHORT II (uLTRA-CHOP): Patients who achieve a complete response to the Smart Stop in Cohort I, receive rituximab IV over 4-6 hours on day 1, acalabrutinib PO BID on days 1-21, lenalidomide QD on days 1-10, and tafasitamab IV over 2 hours on days 1, 8, and 15. Treatments repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive cyclophosphamide IV over 1 hour, doxorubicin hydrochloride IV over 15 minutes, vincristine IV over 15 minutes on day 1, and prednisone PO QD on days 1-5. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progr

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a study of 56 adults with newly diagnosed diffuse large B-cell lymphomas (DLBCL), replacing vindesine with vincristine in the modified R-ACVBP protocol resulted in an 80% complete response rate and an 87% overall survival rate after 2 years.

The treatment was associated with manageable side effects, including anemia and febrile neutropenia, suggesting that mR-ACVBP is a feasible alternative to the original protocol, but further validation in larger trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Regimen for the Treatment of Large B Cell Lymphomas. El Sayed, R., El Darsa, H., Kort, J., et al.[2022]

Rituximab, an anti-CD20 monoclonal antibody, significantly improves tumor remission and patient survival when used in combination with chemotherapy for patients with B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), based on phase III trials.

The drug is generally well tolerated and has been shown to prolong remission when used as maintenance therapy, making it a valuable treatment option included in current guidelines for advanced-stage B-cell NHL and CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on rituximab in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Cvetković, RS., Perry, CM.[2018]

Rituximab, when added to standard chemotherapy, significantly improved survival rates in patients with non-Hodgkin's lymphoma.

In patients with chronic B-cell lymphocytic leukemia, the addition of rituximab to fludarabine-based regimens enhanced both response rates and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the safety and feasibility of rapid infusion of rituximab. Atmar, J.[2022]

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., et al.[2021]

In a randomized trial involving 635 patients aged 61 to 69 with poor-risk aggressive lymphoma, the ACVBP chemotherapy regimen resulted in a higher 5-year overall survival rate of 46% compared to 38% for the standard CHOP regimen.

Although the ACVBP treatment had a higher rate of treatment-related deaths (13% vs. 7% for CHOP), it also showed improved event-free survival (39% vs. 29% for CHOP) and reduced CNS progression or relapse rates, indicating its efficacy despite increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Tilly, H., Lepage, E., Coiffier, B., et al.[2022]

Vinflunine, a new derivative of vinorelbine, shows strong antitumor activity and has demonstrated synergistic effects when combined with drugs like cisplatin, doxorubicin, and 5-fluorouracil in preclinical studies.

The study involved in vitro testing on human cancer cell lines, including A549 lung cancer cells and CCRF-CEM leukemia cells, suggesting that vinflunine could enhance the effectiveness of existing chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro synergistic effects of vinflunine, a novel fluorinated vinca alkaloid, in combination with other anticancer drugs. Barret, JM., Etiévant, C., Hill, BT.[2022]

Vinflunine (VFL) demonstrates significant radiosensitising properties across four human tumor cell lines, with dose enhancement factors ranging from 1.57 to 2.29, indicating its potential to enhance the effectiveness of radiation therapy.

VFL treatment leads to a concentration-dependent block in the G2/M phase of the cell cycle, which may contribute to its radiosensitising effects, while showing no similar effects in normal fibroblast cells, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell cycle effects of vinflunine, the most recent promising Vinca alkaloid, and its interaction with radiation, in vitro. Simoens, C., Vermorken, JB., Korst, AE., et al.[2013]

In a multicentric trial involving 106 women with early-stage breast cancer, two chemotherapy combinations (AC and CMF) were compared, showing similar toxicity profiles except for a significant difference in hair loss, with 100% of patients in the AC group experiencing alopecia.

Preliminary results indicate no significant differences in efficacy between the AC and CMF treatment groups after four cycles of chemotherapy, suggesting both regimens may be equally effective in the adjuvant treatment of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of adjuvant chemotherapy in breast carcinoma with a combination of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and AC (doxorubicin, cyclophosphamide). Initial results of a national cooperative study]. Pribylová, O., Petruzelka, L., Honová, H., et al.[2013]

In a study of 33 patients with HER2-positive metastatic breast cancer who had previously been treated with anthracyclines and taxanes, the combination of vinorelbine and trastuzumab showed an overall response rate of 30.3% and a median overall survival of 12.4 months.

The treatment demonstrated a favorable safety profile, with low rates of severe side effects; only 7.2% experienced grade ≥3 neutropenia, and there were no serious cardiac toxicities or treatment-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes. Lee, YR., Huh, SJ., Lee, DH., et al.[2021]

Capecitabine alone was associated with a significantly higher incidence of nausea and vomiting compared to doxorubicin + paclitaxel, doxorubicin alone, and paclitaxel alone in patients with metastatic/advanced breast cancer, indicating it may be less tolerable for patients.

The doxorubicin + cyclophosphamide regimen showed a lower incidence of febrile neutropenia compared to the doxorubicin + docetaxel regimen, suggesting it may be a safer option regarding this specific toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic/advanced breast cancer. Zhang, XH., Hao, S., Gao, B., et al.[2018]

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

Rituximab is a highly effective monoclonal antibody for treating various B-cell lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, demonstrating a strong activity with low toxicity.

The combination of rituximab with chemotherapy (R-CHOP) has shown the highest efficacy reported for any chemotherapy regimen in treating diffuse large B-cell lymphoma and follicular lymphoma, although some patients may still be resistant to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab therapy in malignant lymphoma. Coiffier, B.[2022]

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard treatment for relapsed diffuse large B-cell lymphoma, but the addition of rituximab has improved outcomes after first-line treatment and relapses.

The CORAL trial found no significant difference in response rates between two salvage regimens (R-ICE and R-DHAP), and identified that factors like early relapse and certain genetic markers significantly affect survival, indicating that over 70% of patients may not benefit from standard salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Gisselbrecht, C.[2022]

In the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

References

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

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Regimen for the Treatment of Large B Cell Lymphomas. [2022]

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

Spotlight on rituximab in non-Hodgkin lymphoma and chronic lymphocytic leukemia. [2018]

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

Review of the safety and feasibility of rapid infusion of rituximab. [2022]

4. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

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

Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

In vitro synergistic effects of vinflunine, a novel fluorinated vinca alkaloid, in combination with other anticancer drugs. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Cell cycle effects of vinflunine, the most recent promising Vinca alkaloid, and its interaction with radiation, in vitro. [2013]

8. Czech Republic pubmed.ncbi.nlm.nih.gov

[Comparison of adjuvant chemotherapy in breast carcinoma with a combination of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and AC (doxorubicin, cyclophosphamide). Initial results of a national cooperative study]. [2013]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes. [2021]

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

A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic/advanced breast cancer. [2018]

11. Japan pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. [2015]

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

Rituximab therapy in malignant lymphoma. [2022]

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

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? [2022]

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

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. [2021]

15. England pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. [2019]