Combination Therapy for Lymphoma

Recruiting at 15 trial locations

Overseen By Annette Hay

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Canadian Cancer Trials Group

Must not be taking: Live vaccines

Disqualifiers: Other malignancies, CNS involvement, HIV, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days per cycle, multiple cycles

129 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug combination therapy for lymphoma?

Research shows that combinations including drugs like dexamethasone, etoposide, and cisplatin have been effective in treating aggressive non-Hodgkin's lymphoma, with some patients achieving complete responses. Additionally, regimens with rituximab have shown excellent results for certain types of lymphoma. ^{1 2 3 4 5}

Is the combination therapy for lymphoma generally safe in humans?

The combination therapy involving drugs like Cisplatin and Etoposide has shown moderate to severe side effects, including nausea, vomiting, kidney issues, nerve damage, and blood cell problems. Cisplatin, in particular, can cause serious side effects like kidney damage, hearing loss, and nerve damage, and requires careful monitoring during treatment. ^{6 7 8 9 10}

What makes the combination therapy for lymphoma unique?

This combination therapy for lymphoma is unique because it includes a mix of drugs like cisplatin, cyclophosphamide, and ibrutinib, which are not typically used together in standard treatments. It targets lymphoma with a multi-faceted approach, potentially offering benefits for patients who have not responded to conventional therapies. ^{2 3 11 12 13}

What is the purpose of this trial?

The purpose of this study is to find out what effects new combinations of treatment will have this disease. New promising treatment strategies will be added to this study as they are available to be compared against the standard treatment.

Research Team

John Kuruvilla

Principal Investigator

Univ. Health Network-Princess Margaret Hospital, Toronto ON Canada

Michael Crump

Principal Investigator

Univ. Health Network-OCI/Princess Margaret Hospital, Toronto ON Canada

Eligibility Criteria

This trial is for people over 16 and under 65 with aggressive B-cell lymphoma that's come back or hasn't responded to treatment. They should have had only one prior therapy (up to three if the cancer transformed from a low-grade type). Participants need measurable disease, good organ function, and an ECOG status of 0-2, indicating they can handle intensive chemotherapy. Women must use birth control or be post-menopausal.

Inclusion Criteria

Clinically and/or radiologically measurable disease

Laboratory Requirements within specified ranges

Life expectancy > 90 days

Exclusion Criteria

I have had cancer before, but it fits the exceptions listed.

I do not have HIV, active Hepatitis B or C, or any uncontrolled infections.

I have not received any live vaccines in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive novel combination therapies compared against standard treatment (R-GDP) for relapsed and refractory aggressive B-cell lymphoma

21 days per cycle, multiple cycles

Multiple visits per cycle for drug administration

Follow-up

Participants are monitored for safety, tolerability, and effectiveness after treatment

2 years

Ongoing monitoring with annual reporting

Safety Run-in

Initial safety assessment for the first six patients assigned to ibrutinib plus R-GDP

Initial phase within treatment

Treatment Details

Interventions

• Cisplatin
• Cyclophosphamide
• Dexamethasone
• Etoposide
• G-CSF
• Gemcitabine
• Ibrutinib
• Mesna
• Rituximab
• Selinexor

Trial Overview The study tests new combinations of drugs against standard treatments for relapsed/refractory aggressive B-cell lymphoma. Drugs include Cyclophosphamide, Rituximab, Etoposide, Cisplatin, Dexamethasone, Selinexor, Gemcitabine, Mesna, Ibrutinib & G-CSF. The goal is to see how these combinations affect the disease.

Participant Groups

Group I: Selinexor + R-GDP Experimental Treatment 5 Interventions

Selinexor - 40mg PO, D1, D3, D8 Rituximab - 375 mg/m2 IV, 1.5 - 6 hours D1 (prior to cisplatin); Gemcitabine - 1000 mg/m2, IV 30 min D1, D8; Dexamethasone - 40 mg daily PO D1 - D4; Cisplatin - 75 mg/m2 IV, 1 hour D1;

Group II: R-DICEP (ACCRUAL COMPLETE) Experimental Treatment 6 Interventions

Rituximab 375 mg/m2 IV 1.5-6hrs Day 1 and Day 5 prior to Cisplatin Mesna 1.75 g/m2 IV 24 hour Cycle 1, Day 2, Day 3 and Day 4 Cyclophosphamide, 1.75 g/m2 IV 2 hours, Day 2, Day 3 and Day 4 Etoposide 350 mg/m2 IV 2 hours, Day 2, Day 3 and Day 4 Cisplatin 35 mg/m2 IV, 2 hours, Day 2, Day 3 and Day 4 G-CSF 300 mcg (\<60kg); 480 mcg (60-90kg); 600 mcg (\>90kg); SC, Daily, starting Day 15 until apheresis completed.

Group III: Ibrutinib plus R-GDP (ACCRUAL COMPLETE) Experimental Treatment 5 Interventions

Ibrutinib 560 mg PO -- D1 - D21 Rituximab 375 mg/m2 IV 1.5 - 6 hours D1 (prior to cisplatin) Gemcitabine 1000 mg/m2 IV 30 min D1, D8 Dexamethasone 40 mg daily PO -- D1 - D4 Cisplatin 75 mg/m2 IV 1 hour D1

Group IV: R-GDP Active Control 4 Interventions

Rituximab - 375 mg/m2 IV, 1.5 - 6 hours D1 (prior to cisplatin); Gemcitabine - 1000 mg/m2, IV 30 min D1, D8; Dexamethasone - 40 mg daily PO D1 - D4; Cisplatin - 75 mg/m2 IV, 1 hour D1;

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Canadian Cancer Trials Group

Lead Sponsor

Trials

135

Recruited

70,300+

Janssen, LP

Industry Sponsor

Trials

169

Recruited

329,000+

Founded

1953

Headquarters

Beerse, Belgium

Known For

Mental Health Therapies

Top Products

Imodium, Remicade, Invega, Procrit

Joaquin Duato

Janssen, LP

Chief Executive Officer since 2022

MBA from ESADE Business School

Biljana Naumovic

Janssen, LP

Chief Medical Officer since 2023

MD from Belgrade University Medical School

Roche Pharma AG

Industry Sponsor

Trials

413

Recruited

430,000+

Dr. Thomas Schinecker

Roche Pharma AG

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Dr. Levi Garraway

Roche Pharma AG

Chief Medical Officer since 2019

MD from University of California, San Francisco

Karyopharm Therapeutics Inc

Industry Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

Findings from Research

The DNCE regimen (which includes DXM, NVB, DDP, and Vp-16) shows comparable efficacy to the DICE regimen (DXM, IFO, DDP, and Vp-16) in treating refractory or relapsed aggressive non-Hodgkin lymphoma, with similar response rates but no statistically significant differences.

Patients receiving the DNCE regimen experienced significantly less bone marrow toxicity compared to those on the DICE regimen, making DNCE a safer second-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[DNCE regimen for treatment of refractory or relapsed aggressive and highly aggressive non-Hodgkin lymphoma]. Liu, XM., Wang, HQ., Zhang, HL., et al.[2018]

In a study of 30 patients with refractory or relapsing non-Hodgkin's lymphoma, the DVIP treatment led to a 33% complete response rate and a 30% partial response rate, with responses lasting from 2.5 to over 24 months.

While DVIP treatment caused significant myelosuppression, it was considered safe as there were no drug-related deaths, indicating it is an effective salvage therapy for aggressive forms of NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage therapy for non-Hodgkin's lymphoma with a combination of dexamethasone, etoposide, ifosfamide, and cisplatin. Haim, N., Rosenblatt, E., Wollner, M., et al.[2019]

New chemotherapy combinations, such as IMVP-16 and MIME, have shown promising results in lymphoma patients, achieving overall response rates of 60% and complete response rates of 25%.

Long-term follow-up of the MIME regimen indicates a 25% cure rate for intermediate-grade lymphoma patients who achieve a complete response, highlighting its potential effectiveness as a salvage treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with salvage regimens at M.D. Anderson Hospital. Cabanillas, F.[2020]

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]

The ESHAOx regimen, which replaces cisplatin with oxaliplatin, showed a 63% overall response rate in 27 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma, indicating its potential effectiveness as a treatment option.

While the treatment resulted in significant hematologic toxicities like neutropenia (56%) and thrombocytopenia (35%), it did not cause severe renal or neurotoxicity, suggesting a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin's lymphoma. Sym, SJ., Lee, DH., Kang, HJ., et al.[2018]

In a study of 26 patients with refractory or recurrent lymphoma, the combination of cis-platinum, VP-16, and MGBG resulted in a 20% complete remission rate and a 40% partial remission rate among non-Hodgkin's lymphoma patients, indicating some efficacy of this treatment regimen.

The treatment was associated with significant toxicity, including severe side effects like leukopenia, thrombocytopenia, and profound peripheral neuropathy, which led to treatment discontinuation in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, VP-16-213 and MGBG (methylglyoxal bis guanylhydrazone) combination chemotherapy in refractory lymphoma, a phase II study. Dabich, L., Liepman, MK.[2019]

Carboplatin, a platinum analogue of cisplatin, shows comparable antitumor activity against various cancers while significantly reducing renal and neurotoxic side effects, making it a safer alternative.

Preliminary studies on iproplatin indicate it may also have reduced renal and neurologic toxicity similar to carboplatin, with efficacy comparable to cisplatin, suggesting it could be another promising option in chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and II agents in cancer therapy: two cisplatin analogues and high-dose cisplatin in hypertonic saline or with thiosulfate protection. Fuks, JZ., Wadler, S., Wiernik, PH.[2019]

Cisplatin is a widely used cancer treatment but can cause serious dose-dependent toxicities, including nausea, renal insufficiency, and myelosuppression, especially in cases of overdose.

There are currently no specific antidotes for cisplatin overdose, but management strategies include aggressive hydration, monitoring, and supportive therapies, with some experimental treatments showing limited effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin overdose: toxicities and management. Tsang, RY., Al-Fayea, T., Au, HJ.[2022]

Cis-dichlorodiammineplatinum(II) can cause serious side effects such as nephrotoxicity, gastrointestinal issues (like nausea and vomiting), and myelosuppression, highlighting the need for careful monitoring during treatment.

Other potential side effects include ototoxicity (which can lead to hearing loss), anaphylactic reactions, and peripheral neuropathies, indicating that while the drug may be effective, its safety profile requires close attention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic effects of cis-dichlorodiammineplatinum(II) in man. Von Hoff, DD., Schilsky, R., Reichert, CM., et al.[2022]

A 60-year-old woman with squamous lung carcinoma experienced paroxysmal supraventricular tachycardia during treatment with cisplatin and etoposide, highlighting a potential cardiac side effect of cisplatin.

The case suggests that caution should be exercised when administering cisplatin to patients with existing cardiac conditions or those who have received other cardiotoxic cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paroxysmal supraventricular tachycardia during treatment with cisplatin and etoposide combination. Fassio, T., Canobbio, L., Gasparini, G., et al.[2018]

Cisplatin and carboplatin have shown effective responses in treating non-Hodgkin's lymphomas, particularly in cases of primary resistance or relapses, with cisplatin-based combinations prolonging survival in 30-40% of patients.

Effective antiemetic therapies, like ondansetron and granisetron, have reduced the fear of vomiting associated with these treatments, leading to increased use of cisplatin and carboplatin combinations in resistant malignant lymphoproliferative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cisplatin and carboplatin in the treatment of malignant lymphoma and multiple myeloma]. Adam, Z., Mayer, J., Hájek, R.[2013]

In a study of 97 patients with advanced malignant lymphomas resistant to previous chemotherapy, the combination chemotherapy regimens V-PLAT and V-HEX showed limited antitumor activity, with objective response rates of 20% and 8%, respectively.

Despite the higher toxicity associated with V-PLAT, particularly hematologic toxicity, the overall median survival for patients was approximately 6 months, indicating that neither regimen significantly improved outcomes compared to previous treatments with VM-26 or hexamethylmelamine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative trial of two teniposide-based combination chemotherapy regimens for the treatment of advanced malignant lymphomas. O'Connell, MJ., Anderson, J., Merrill, JM., et al.[2013]

The DVIP regimen (dexamethasone, etoposide, ifosfamide, and cisplatin) demonstrated a significant response rate in patients with aggressive non-Hodgkin's lymphoma, achieving a complete response in 32% of the 56 patients studied, with a median survival of 30 months for those who achieved complete response.

Age and prior treatment response were identified as key predictors of treatment success, with younger patients and those who responded well to previous therapies having better outcomes, while myelosuppression was the main side effect observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone, etoposide, ifosfamide, and cisplatin as second-line therapy in patients with aggressive non-Hodgkin's lymphoma. Haim, N., Ben-Shahar, M., Faraggi, D., et al.[2019]

References

1. China pubmed.ncbi.nlm.nih.gov

[DNCE regimen for treatment of refractory or relapsed aggressive and highly aggressive non-Hodgkin lymphoma]. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Salvage therapy for non-Hodgkin's lymphoma with a combination of dexamethasone, etoposide, ifosfamide, and cisplatin. [2019]

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

Experience with salvage regimens at M.D. Anderson Hospital. [2020]

4. 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]

5. Germany pubmed.ncbi.nlm.nih.gov

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin's lymphoma. [2018]

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

Cisplatin, VP-16-213 and MGBG (methylglyoxal bis guanylhydrazone) combination chemotherapy in refractory lymphoma, a phase II study. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Phase I and II agents in cancer therapy: two cisplatin analogues and high-dose cisplatin in hypertonic saline or with thiosulfate protection. [2019]

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

Cisplatin overdose: toxicities and management. [2022]

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

Toxic effects of cis-dichlorodiammineplatinum(II) in man. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Paroxysmal supraventricular tachycardia during treatment with cisplatin and etoposide combination. [2018]

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

[Cisplatin and carboplatin in the treatment of malignant lymphoma and multiple myeloma]. [2013]

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

Comparative trial of two teniposide-based combination chemotherapy regimens for the treatment of advanced malignant lymphomas. [2013]

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

Dexamethasone, etoposide, ifosfamide, and cisplatin as second-line therapy in patients with aggressive non-Hodgkin's lymphoma. [2019]