Tolinapant + Decitabine/Cedazuridine for Peripheral T-Cell Lymphoma

Recruiting at 52 trial locations

Overseen By Astex Pharmaceuticals, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Taiho Oncology, Inc.

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with peripheral T-cell lymphoma, a cancer affecting the immune system. The goal is to determine a safe dose and evaluate the effectiveness of the treatments together. It involves two oral drugs: tolinapant (an experimental treatment) and decitabine/cedazuridine. Suitable candidates for this trial include those with specific subtypes of this lymphoma who have undergone at least two previous treatments but still experience worsening symptoms. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot use certain medications like CYP3A4 inhibitors/inducers within 2 weeks of starting the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

Research has shown that tolinapant, when used alone, has a manageable safety profile for patients with relapsed or hard-to-treat peripheral T-cell lymphoma (PTCL). While some side effects were reported, they were generally controllable. In earlier studies, patients tolerated the treatment fairly well, with some experiencing common side effects like tiredness or nausea.

Previous studies have focused on confirming the safety of the decitabine and cedazuridine combination, especially for PTCL patients. This combination is already approved for other conditions, indicating a certain level of safety. Current trials aim to ensure its safety for PTCL patients as well.

In summary, both tolinapant and the decitabine/cedazuridine combination have demonstrated promising safety results in past studies. While side effects can occur, they are often manageable, and the treatments are generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they bring a fresh approach to fighting peripheral T-cell lymphoma. Unlike standard chemotherapy treatments like CHOP or ICE, Tolinapant works by inhibiting a protein that helps cancer cells survive, making it a novel mechanism of action. Additionally, the combination of oral Decitabine/Cedazuridine offers a more convenient, pill-based delivery method compared to traditional intravenous chemotherapy, potentially improving patient quality of life. This innovative approach could lead to more effective and patient-friendly treatment options for those battling this challenging cancer.

What evidence suggests that this trial's treatments could be effective for peripheral T-cell lymphoma?

Research has shown that tolinapant effectively treats certain types of T-cell lymphoma, specifically peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). One study demonstrated promising results with tolinapant alone, as more than 20% of patients with recurring or hard-to-treat PTCL showed improvement. In this trial, participants in one arm will receive tolinapant combined with the oral medication decitabine/cedazuridine. Previous studies have shown that this combination resulted in 60% of patients responding to the treatment, with 21% achieving a complete response, meaning their cancer was no longer detectable. These findings suggest that this treatment combination could be effective for PTCL. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for people with a specific type of cancer called Peripheral T-cell Lymphoma (PTCL) that has come back or didn't respond to treatment. They should have tried at least two treatments before, be expected to live more than 12 weeks, and not be pregnant or breastfeeding. They can't join if they've had certain heart problems, uncontrolled infections, significant mental illness or substance abuse issues, other active cancers needing treatment (except some breast/prostate/bladder cancers), recent other cancer treatments like chemotherapy or CAR-T therapy within specified time frames, known HIV/HBV/HCV infection, CNS lymphoma history, allogeneic transplant history or autotransplant within the last 100 days.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My cancer is a type of T-cell lymphoma confirmed by tests.

I am not pregnant or breastfeeding and my pregnancy test was negative.

Exclusion Criteria

I have a history of heart problems or am at risk for them.

I have been diagnosed with lymphoma in my central nervous system.

Known significant mental illness or active substance abuse

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive tolinapant in combination with oral decitabine/cedazuridine to determine the recommended phase 2 dose (RP2D)

28-day cycles

Visits as per cycle schedule

Phase 2 Treatment

Participants receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine

28-day cycles

Visits as per cycle schedule

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 54 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine + Cedazuridine
• Tolinapant

Trial Overview The study is testing how safe and effective a drug named Tolinapant is when given with an oral combination of Decitabine/Cedazuridine in patients with PTCL. The first phase will find the best dose to use while checking safety; the second phase will see how well it works by measuring response rates.

How Is the Trial Designed?

Group I: Phases 1 and 2: Tolinapant + Oral Decitabine/Cedazuridine Experimental Treatment 2 Interventions

Tolinapant, orally, once daily (QD) on Days 1 to 7 and 15 to 21 of each 28-day cycle in combination with oral decitabine/cedazuridine fixed-dose combination (FDC) tablet, QD on days determined by the Lead-in Phase during each 28-day cycle. The starting dose of tolinapant will be escalated stepwise in successive cohorts until the RP2D is determined. Based on RP2D and results determined from Phase 1 participants would receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine, FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle in Phase 2.

Group II: Phase 1: Oral Decitabine/Cedazuridine Experimental Treatment 1 Intervention

Decitabine/cedazuridine FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle.

Who Is Running the Clinical Trial?

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Astex Pharmaceuticals, Inc.

Lead Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Published Research Related to This Trial

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

Oral azacitidine (CC-486) has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia who are in complete remission, highlighting its efficacy in this specific patient population.

The combination of decitabine and cedazuridine (ASTX727) is approved for treating adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, particularly those with intermediate-1 or higher risk, indicating its targeted therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Kipp, D., H Wei, A.[2022]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10429443/

PB2358: PHASE 1-2 STUDY OF THE SAFETY, PK, PD ... An ongoing Phase 1-2 study demonstrates an overall response rate (ORR) of >20% in relapsed/refractory PTCL with single agent tolinapant.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05403450

A Study of Tolinapant in Combination With Oral Decitabine ... Based on RP2D and results determined from Phase 1 participants would receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine, FDC ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05403450?term=Cedazuridine&viewType=Table&rank=7

A Study of Tolinapant in Combination With Oral Decitabine ... The primary purpose of the study is to assess safety, and to identify the recommended phase 2 dose (RP2D) of tolinapant in combination with oral decitabine/ ...

4. journals.lww.com journals.lww.com/hemasphere/fulltext/2023/08003/pb2358__phase_1_2_study_of_the_safety,_pk,_pd,_and.2211.aspx

PB2358: PHASE 1-2 STUDY OF THE ... An ongoing Phase 1-2 study demonstrates an overall response rate (ORR) of >20% in relapsed/refractory PTCL with single agent tolinapant.

5. withpower.com withpower.com/trial/phase-2-lymphoma-t-cell-peripheral-5-2022-b85b4

Tolinapant + Decitabine/Cedazuridine for Peripheral T-Cell ... Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46 ...

6. clinicaltrials.eu clinicaltrials.eu/trial/study-of-tolinapant-with-decitabine-and-cedazuridine-for-patients-with-relapsed-or-refractory-peripheral-t-cell-lymphoma/

Study of Tolinapant with Decitabine and Cedazuridine for ... The purpose of the study is to find out how safe these treatments are and how well they work in treating R/R PTCL. The study will be conducted ...

7. astx.com astx.com/2022-tclf-trials-in-progress-a-phase-1-2-open-label-study-of-the-safety-pharmacokinetics-pharmacodynamics-and-preliminary-activity-of-tolinapant-in-combination-with-oral-decitabine-cedazuridine/

2022 TCLF: Trials-In-Progress, A Phase 1-2, Open-Label ... There is a lead-in phase to confirm tolerability of the MDS-approved regimen of oral decitabine/cedazuridine is tolerated in a PTCL population.