Selinexor + R-GDP for Lymphoma

Recruiting at 20 trial locations

Overseen By Karyopharm Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Karyopharm Therapeutics Inc

Must not be taking: XPO1 inhibitors

Disqualifiers: MALT lymphoma, CNS involvement, others

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

Compensation: Varies

Number of Visits: 2

501 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL), a type of blood cancer. The study aims to determine if adding the drug selinexor to the standard treatment regimen, R-GDP, is safe and effective. Participants will be divided into groups to receive either the new treatment combination or the standard treatment, and the trial will assess which is more effective. Those who have experienced a return of DLBCL or have not responded to treatment, and who are not planning to undergo stem cell or CAR-T therapy, might be suitable candidates for this trial. As a Phase 2, Phase 3 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in cancer treatment.

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, you cannot use any standard or experimental anti-DLBCL therapy within 21 days before starting the trial, except for low-dose prednisone or palliative radiation on non-target lesions.

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

Studies have shown that the combination of selinexor and R-GDP is generally safe and manageable for patients with relapsed or hard-to-treat B-cell non-Hodgkin lymphoma. In a previous study, most patients tolerated weekly doses of selinexor well. Common side effects included nausea, tiredness, and low blood cell counts, which could be managed with supportive care.

Additionally, selinexor has already received approval for treating multiple myeloma, indicating that health authorities have reviewed and accepted its safety for use in people. This existing approval provides some reassurance about its safety.

Overall, the treatment appears to be fairly well-tolerated, with some expected side effects that are usually manageable. However, discussing any concerns with a healthcare provider before joining a clinical trial is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Selinexor in combination with R-GDP for treating relapsed/refractory diffuse large B-cell lymphoma (RR DLBCL) because Selinexor offers a unique approach. Unlike standard treatments, which often focus on killing cancer cells directly, Selinexor works by blocking the export of tumor-suppressing proteins out of the cell nucleus, essentially trapping them where they can fight the cancer more effectively. This novel mechanism of action, combined with its potential oral administration, presents a promising alternative that could enhance the effectiveness of existing therapies for patients who have not responded well to current options.

What evidence suggests that this trial's treatments could be effective for RR DLBCL?

In this trial, participants will receive different treatments to evaluate their effectiveness in treating relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL). One treatment arm combines selinexor with R-GDP, which previous studies have shown to lead to significant response rates, with many patients experiencing tumor shrinkage. Selinexor blocks a protein that cancer cells need to grow, helping to manage the disease. Research has shown that selinexor is effective when used alone or with other treatments like R-GDP. These findings offer hope that this treatment can be effective for people with RR DLBCL. Other participants in this trial will receive a placebo with R-GDP or R-GDP alone to compare the outcomes. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for patients with relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) who have had 1-3 prior systemic therapies but are not candidates for stem cell transplant or CAR-T therapy. They must have measurable disease, adequate organ function, and agree to contraception. Exclusions include central nervous system involvement by DLBCL, recent major surgery or stem cell transplant/CAR-T therapy, uncontrolled infections, certain viral infections without controlled load, inability to swallow tablets, pregnancy/breastfeeding.

Inclusion Criteria

My blood tests show my bone marrow is working well.

My maintenance therapy is not considered a separate treatment.

I am not planned for stem cell or CAR-T cell therapy as decided by my doctor.

Exclusion Criteria

I have hepatitis B but have been on antiviral therapy for over 8 weeks and my viral load is under 100 IU/mL.

I had my own stem cell transplant less than 100 days ago or a donor's less than 180 days ago.

My diffuse large B-cell lymphoma has spread to my brain or its coverings.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 2

Participants receive selinexor (40 mg or 60 mg) in combination with R-GDP for up to 6 cycles (21-day per cycle)

18 weeks

Visits on Days 1, 2, 3, 4, and 8 of each cycle

Treatment Phase 3

Participants receive the selected dose of selinexor from Phase 2 in combination with R-GDP for up to 6 cycles (21-day per cycle), followed by selinexor 60 mg or placebo

18 weeks

Visits on Days 1, 2, 3, 4, and 8 of each cycle

Continuous Therapy

Participants who reach partial or complete response receive selinexor 60 mg or placebo as single-agent continuous therapy until progressive disease or unacceptable toxicity

Until PD or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Dexamethasone
• Gemcitabine
• Placebo matching for Selinexor (combination therapy)
• Placebo matching for Selinexor (continuous therapy)
• Rituximab
• Selinexor

Trial Overview The study tests Selinexor combined with Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) against standard R-GDP plus placebo in patients with RR DLBCL. It includes a Phase 2 part to determine the best dose of Selinexor and a Phase 3 part comparing this dose with placebo. Treatment lasts up to six cycles of 21 days each.

How Is the Trial Designed?

Group I: Phase 3: Selinexor (Selected Dose) + R-GDP followed by Selinexor 60 mg Experimental Treatment 6 Interventions

Patients with RR DLBCL will receive combination therapy of selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by selinexor 60 mg orally QW for each 28-day cycle until PD or unacceptable toxicity.

Group II: Phase 3: Selinexor (Selected Dose) + R-GDP followed by Placebo Experimental Treatment 6 Interventions

Patients with RR DLBCL will receive combination therapy of selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by matching placebo for selinexor orally QW for each 28-day cycle until PD or unacceptable toxicity.

Group III: Phase 2: Selinexor 60 mg + R-GDP Experimental Treatment 6 Interventions

Patients with RR DLBCL will receive combination therapy of selinexor 60 mg orally at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by single-agent continuous therapy with selinexor 60 mg orally QW for each 28-day cycle until PD or unacceptable toxicity.

Group IV: Phase 2: Selinexor 40 mg + R-GDP Experimental Treatment 6 Interventions

Patients with RR DLBCL will receive combination therapy of selinexor 40 mg orally at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by single-agent continuous therapy with selinexor 60 mg orally once weekly (QW) for each 28-day cycle until progressive disease (PD) or unacceptable toxicity.

Group V: Phase 2: R-GDP Active Control 4 Interventions

Patients with RR DLBCL will receive R-GDP on specified days (Days 1, 2, 3, 4, and 8) for each 21-day cycle for up to 6 cycles.

Group VI: Phase 3: Placebo + R-GDP followed by Placebo Placebo Group 6 Interventions

Patients with RR DLBCL will receive combination therapy of placebo matching for selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by matching placebo for selinexor orally QW for each 28-day cycle until PD or unacceptable toxicity.

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?

Karyopharm Therapeutics Inc

Lead 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

Published Research Related to This Trial

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]

Two new analogues of cisplatin, specifically the enantiomers of cis-dichloro(1,4-diamino-1,4-dideoxy-2,3-O-isopropylidenethreitol)-platinum(II), demonstrated a higher therapeutic index (TI) than cisplatin in treating ADJ/PC6 plasmacytoma in mice.

These new compounds not only showed effective antitumor activity when given by intraperitoneal injection but also maintained significant efficacy when administered orally, suggesting a promising alternative to traditional cisplatin treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analogues of cisplatin derived from diaminodideoxytetritols. Synthesis and activity against the ADJ/PC6 plasmacytoma in mice. Haines, AH., Morley, C., Murrer, BA.[2019]

Cisplatin (CDDP) alone effectively reduced tumor growth in a human yolk sac tumor model in nude mice, but higher doses led to significant toxicity in the host.

Co-administering selenium with CDDP did not reduce its anti-tumor effects and significantly decreased host toxicity, allowing for higher doses of CDDP to be used safely, which could enhance its therapeutic potential in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of co-administration of selenium and cis-platin (CDDP) on CDDP-induced toxicity and antitumour activity. Ohkawa, K., Tsukada, Y., Dohzono, H., et al.[2019]

Selinexor, an exportin-1 inhibitor, has received regulatory approval for treating multiple myeloma and non-Hodgkin lymphomas based on pivotal trials, including the SADAL and BOSTON trials, demonstrating its potential as a monotherapy or in combination regimens.

While selinexor shows promise in overcoming treatment resistance and may have synergistic effects with other therapies, it has consistent tolerability issues, necessitating improved management strategies to enhance its efficacy compared to newer cellular and immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor therapy for multiple myeloma and non-Hodgkin lymphomas. Goldsmith, SR., Liu, L., Shiah, K.[2023]

Selinexor (XPOVIO™) is a novel oral medication that inhibits Exportin-1 (XPO1) and has been approved for treating relapsed or refractory multiple myeloma (RRMM) in adults, marking a significant advancement in cancer therapy.

The drug is currently being tested for effectiveness in various other types of blood and solid tumors, indicating its potential as a versatile treatment option in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor: First Global Approval. Syed, YY.[2023]

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]

In a phase 1 trial involving 79 patients with relapsed or refractory non-Hodgkin lymphoma, selinexor demonstrated a safety profile with common side effects including thrombocytopenia and neutropenia, but it was well-tolerated overall.

Selinexor showed promising efficacy, with 31% of evaluable patients achieving objective responses, including 4 complete responses, indicating that it may be a viable treatment option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma. Kuruvilla, J., Savona, M., Baz, R., et al.[2021]

In a phase I study involving 11 patients with relapsed/refractory T-cell lymphoma and natural-killer/T-cell lymphoma, the maximum tolerated dose (MTD) of selinexor combined with high-dose dexamethasone and chemotherapy was determined to be 40 mg, indicating a need for careful dosing due to significant toxicities.

The treatment combination resulted in high overall (91%) and complete response rates (82%) in evaluable patients, suggesting that while effective, the regimen was associated with considerable side effects, including severe thrombocytopenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma Tang, T., Martin, P., Somasundaram, N., et al.[2021]

JM335, a new platinum-based drug, showed comparable cytotoxicity to cisplatin against human ovarian cancer cells and was over 50 times more potent than transplatin, indicating its potential as an effective treatment option.

Unlike cisplatin, JM335 demonstrated non-cross-resistance in most cisplatin-resistant tumor cell lines, suggesting it could be effective in patients who have developed resistance to traditional platinum-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity. Kelland, LR., Barnard, CF., Mellish, KJ., et al.[2016]

The metal complex CTDP demonstrated comparable antitumor activity to cisplatin (DDP) in a sensitive ovarian tumor line, showing significant colony growth reduction at various concentrations, while also exhibiting a potentially better safety profile due to lower toxicity.

The ruthenium complex ICR was the most effective compound against the DDP-resistant ovarian tumor line, outperforming DDP, indicating its potential as a promising treatment option for resistant ovarian cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro evaluation of platinum, titanium and ruthenium metal complexes in cisplatin-sensitive and -resistant rat ovarian tumors. Frühauf, S., Zeller, WJ.[2019]

Lower concentrations of thiophosphate (SPO(3)) can reduce the cytotoxic effects of cisplatin (cDDP) in cancer cells by affecting the activity of thioredoxin reductase 1 (TrxR1), while higher concentrations of SPO(3) exhibit direct cytotoxicity.

Selenium supplementation increases TrxR1 activity in NIH 3T3 cells, leading to decreased reliance on glutathione but heightened susceptibility to cisplatin, indicating that selenium levels can influence drug sensitivity and cellular mechanisms related to oxidative stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiophosphate and selenite conversely modulate cell death induced by glutathione depletion or cisplatin: effects related to activity and Sec contents of thioredoxin reductase. Peng, X., Xu, J., Arnér, ES.[2020]

The combination of the nuclear export inhibitor selinexor with dexamethasone (DEX) or everolimus (EVER) showed enhanced effectiveness against Non-Hodgkin Lymphoma (NHL) in both cell lines and animal models, indicating a promising therapeutic strategy.

Molecular analysis revealed that this combination therapy activates apoptotic signaling and down-regulates the nuclear exporter protein XPO1, supporting the mechanism of action for these drugs and providing a rationale for further clinical testing in Phase II trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor activity of selective inhibitor of nuclear export (SINE) compounds, is enhanced in non-Hodgkin lymphoma through combination with mTOR inhibitor and dexamethasone. Muqbil, I., Aboukameel, A., Elloul, S., et al.[2023]

A study analyzing adverse event reports from 2017 to 2021 identified 1853 effective adverse event signals for three platinum drugs (Cisplatin, Carboplatin, and Oxaliplatin), highlighting the need for careful monitoring of side effects in cancer treatment.

Cisplatin primarily affects the blood and lymphatic systems, Carboplatin is associated with respiratory issues, and Oxaliplatin impacts the nervous system, indicating that each drug has distinct adverse event profiles that should guide individualized treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum drugs-related safety profile: The latest five-year analysis from FDA adverse event reporting system data. Feng, G., Zhou, X., Chen, J., et al.[2023]

Cisplatin therapy is often limited by nephrotoxicity, which can be mild and reversible but may become severe and irreversible at higher doses.

Recent studies suggest that hypertonic NaCl 0.9% may reduce the incidence of nephrotoxicity from cisplatin, and new platinum analogs are being tested to maintain effectiveness while minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin nephrotoxicity: a summary of preventative interventions. Finley, RS., Fortner, CL., Grove, WR.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34132444/

Selinexor for Relapsed or Refractory Diffuse Large B-Cell ... Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL.

2. xpovio.com xpovio.com/dlbcl/clinical-trial

XPOVIO® (selinexor) | RR DLBCL Treatment Response ... Read about the clinical study results and response rates of adults with Relapsed or Refractory diffuse large B-cell lymphoma (RR DLBCL).

3. investors.karyopharm.com investors.karyopharm.com/2020-12-07-Karyopharm-Presents-XPOVIO-R-Selinexor-Data-in-Multiple-Myeloma-and-Diffuse-Large-B-Cell-Lymphoma-at-the-American-Society-of-Hematology-2020-Annual-Meeting

Karyopharm Presents XPOVIO® (Selinexor) Data in ... New subgroup analyses from the Phase 2b SADAL study evaluating XPOVIO in relapsed or refractory diffuse large B-cell lymphoma (DLBCL). "The ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8488790/

FDA Approval Summary: Selinexor for Relapsed or Refractory ... Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL.

5. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6234/506276/Phase-2-Search-Study-XPO1-Inhibitor-ATG-010

Phase 2 Search Study：XPO1 Inhibitor (ATG-010 ... The SEARCH study demonstrates clinically meaningful ORR in Chinese R/R DLBCL pts treated with selinexor monotherapy, consistent with the global study.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04442022

NCT04442022 | A Study of Rituximab-Gemcitabine ... The purpose of this Phase 2/3 study is to evaluate efficacy and safety of the combination of selinexor and R-GDP (SR-GDP) in patients with RR DLBCL.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11311764/

Phase IB Study of Oral Selinexor in Combination with ... The results from our phase I clinical study indicate that weekly selinexor plus RGDP has a generally tolerable safety profile and durable efficacy in R/R B-NHL.

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04442022/

Clinical Trial: NCT04442022 The purpose of this Phase 2/3 study is to evaluate efficacy and safety of the combination of selinexor and R-GDP (SR-GDP) in patients with RR ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121033851

Selinexor in Combination with R-GDP for Patients ... This study established the safety profile of weekly 40mg of Selinexor in combination with R-GDP for R/RB cell lymphoma with an ORR of 67%.

10. xpovio.com xpovio.com/dlbcl

XPOVIO® (selinexor) | Relapsed or Refractory DLBCL XPOVIO (selinexor) is a prescription medicine used in combination with dexamethasone to treat adults with multiple myeloma that has come back (relapsed)