Selinexor + R-GDP for Lymphoma

Recruiting at 22 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

Trial Summary

What is the purpose of this trial?

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 who are not intended to receive hematopoetic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR-T) therapy. This study consists of 3 arms each in Phase 2 and 3. Phase 2 portion of the study will assess the two doses of selinexor (40 milligram \[mg\] or 60 mg) in combination with R-GDP, for up to 6 cycles (21-day per cycle), followed by 60 mg selinexor single agent continuous therapy for those who have reached a partial or complete response. Phase 3 portion of the study will evaluate the selected dose of SR-GDP (identified in Phase 2) versus standard R-GDP + matching placebo, for up to 6 cycles (21-day per cycle), followed by placebo or 60 mg selinexor single agent continuous therapy for those who have reached partial or complete response.

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.

What data supports the effectiveness of the drug Selinexor in combination with other treatments for lymphoma?

Research shows that Selinexor, when combined with dexamethasone, enhances anti-cancer activity in non-Hodgkin lymphoma by promoting cell death and reducing cancer cell growth. In clinical trials, Selinexor demonstrated encouraging responses in patients with relapsed or refractory non-Hodgkin lymphoma, suggesting its potential effectiveness in combination therapies. ^{1 2 3 4 5}

What are the safety concerns associated with the treatment Selinexor + R-GDP for Lymphoma?

Cisplatin, a component of the treatment, can cause serious side effects like kidney damage, nausea, vomiting, hearing loss, and nerve damage. These effects are dose-dependent and require careful monitoring during treatment. ^{6 7 8 9 10}

What makes the drug Selinexor + R-GDP unique for treating lymphoma?

The combination of Selinexor with R-GDP for lymphoma is unique because Selinexor works by inhibiting nuclear export, which is a different mechanism compared to traditional chemotherapy drugs like cisplatin. This novel approach may offer benefits in overcoming resistance to standard treatments. ^{7 11 12 13 14}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Ireland 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. [2023]

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

Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma. [2021]

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

Selinexor therapy for multiple myeloma and non-Hodgkin lymphomas. [2023]

4. Italy 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 [2021]

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

Selinexor: First Global Approval. [2023]

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

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

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

Analogues of cisplatin derived from diaminodideoxytetritols. Synthesis and activity against the ADJ/PC6 plasmacytoma in mice. [2019]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Platinum drugs-related safety profile: The latest five-year analysis from FDA adverse event reporting system data. [2023]

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

Cisplatin nephrotoxicity: a summary of preventative interventions. [2019]

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

Cisplatin overdose: toxicities and management. [2022]

11. England 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. [2020]

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

The effects of co-administration of selenium and cis-platin (CDDP) on CDDP-induced toxicity and antitumour activity. [2019]

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

A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity. [2016]

14. Germany pubmed.ncbi.nlm.nih.gov

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