Tazemetostat + Doxorubicin for Sarcoma

No longer recruiting at 22 trial locations

Overseen By Ipsen Clinical Study Enquiries

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Epizyme, Inc.

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Myeloid malignancies, CNS metastasis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of two treatments, tazemetostat and doxorubicin, to determine their effectiveness in managing advanced epithelioid sarcoma, a rare soft tissue cancer. The trial seeks to identify the safest dose and assess how long the treatment can prevent disease progression. Participants will receive either the combination of tazemetostat and doxorubicin or a placebo with doxorubicin. Individuals with epithelioid sarcoma that cannot be surgically removed and who have measurable disease may be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take medications that strongly affect a liver enzyme called CYP3A4. It's best to discuss your current medications with the trial 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 patients with advanced soft-tissue sarcoma generally tolerate the combination of tazemetostat and doxorubicin well. In one study, most patients managed the treatment without significant issues, though some experienced serious side effects. These included bleeding, fluid around the lungs, skin infections, trouble breathing, pain, and severe respiratory problems.

Tazemetostat already has FDA approval for treating epithelioid sarcoma, indicating a well-understood safety profile. This offers some confidence about its safety when combined with doxorubicin, but individual experiences may vary. It is crucial to discuss potential risks with a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for sarcoma?

Researchers are excited about the combination of tazemetostat and doxorubicin for treating sarcoma because it targets cancer cells in a novel way. Unlike traditional treatments that primarily focus on killing rapidly dividing cells, tazemetostat is an EZH2 inhibitor, which means it interferes with gene expression in cancer cells, potentially stopping their growth. This combination could enhance the effectiveness of doxorubicin, a standard chemotherapy drug, by making the cancer cells more susceptible to treatment. By combining these mechanisms, there's hope for improved outcomes for patients battling sarcoma.

What evidence suggests that tazemetostat in combination with doxorubicin could be an effective treatment for epithelioid sarcoma?

Research has shown that tazemetostat may help treat advanced epithelioid sarcoma by blocking a protein that aids cancer cell growth. Studies have found it effective, with some patients experiencing tumor reduction. When used alone, about 15% of patients responded to the treatment, with some seeing partial or complete improvement. This trial tests the combination of tazemetostat with doxorubicin, a common cancer drug, to determine if the combination works better. Participants in one group will receive tazemetostat and doxorubicin, while another group will receive a placebo with doxorubicin. ^{4 5 6 7 8}

Who Is on the Research Team?

Ipsen Medical Director

Principal Investigator

Ipsen

Are You a Good Fit for This Trial?

Adults with advanced epithelioid sarcoma, a rare soft-tissue cancer, are eligible for this trial if they have measurable disease and an expected lifespan of at least 3 months. They must be able to perform daily activities with minimal assistance (ECOG status 0-2) and have proper organ function. Women can't be pregnant/breastfeeding and along with men, must use effective contraception. Those with HIV may join if well-controlled on therapy. Exclusions include active hepatitis B/C infections, other major illnesses that could interfere with the study, prior cancer treatments or conditions affecting drug absorption.

Inclusion Criteria

My blood, kidney, and liver tests meet the required levels.

I have HIV but it is well controlled with medication.

I am a man who either had a vasectomy or uses effective birth control.

Exclusion Criteria

I have a history of T-cell lymphoblastic lymphoma or leukemia.

I have recovered from major surgery that occurred more than 4 weeks ago.

I am not taking strong medications that affect liver enzymes or St. John's Wort.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Open-label phase to evaluate safety and establish maximum tolerated dose of tazemetostat + doxorubicin

6 cycles (21 days each)

1 visit per cycle (in-person)

Phase 3 Treatment

Double-blind phase comparing tazemetostat + doxorubicin to placebo + doxorubicin

6 cycles (21 days each) followed by continuous 28-day cycles

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Average of two years

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin HCl
• Tazemetostat

Trial Overview The trial is testing tazemetostat in combination with doxorubicin against a placebo combined with doxorubicin in patients who haven't had previous systemic anticancer therapy. Part 1 focuses on determining the safest dose level while part 2 compares how long patients live without their disease worsening using these combinations.

How Is the Trial Designed?

Group I: Phase 1b: Open-label Tazemetostat and Phase 3: Tazemetostat + Doxorubicin Arm Experimental Treatment 2 Interventions

Phase 1b: On cycle 1 day -1, participants will receive a single morning dose of tazemetostat at the assigned dose level. Participants will receive doxorubicin 75 mg/m2 intravenously (IV) on day 1 of each cycle for up to 6 cycles. Tazemetostat will be escalated from a starting dose of 400 mg twice daily PO to 600 mg twice daily PO to 800 mg twice daily. Phase 3: Tazemetostat (800 mg) administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycle 7 and beyond. Doxorubicin 75 mg/m2 IV on day 1 of cycles 1-6.

Group II: Phase 3: Placebo + Doxorubicin Arm Placebo Group 2 Interventions

Placebo administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycles 7 and beyond. Doxorubicin 75 mg/m2 IV on day 1 of cycles 1-6.

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

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma
• Sarcoma

Approved in United States as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma
• Sarcoma
• Multiple myeloma

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma
• Sarcoma

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma
• Sarcoma

Who Is Running the Clinical Trial?

Epizyme, Inc.

Lead Sponsor

Trials

34

Recruited

2,800+

Published Research Related to This Trial

Tazemetostat (Tazverik™) is the first approved treatment specifically for adults and adolescents aged 16 years and older with locally advanced or metastatic epithelioid sarcoma, receiving accelerated approval in January 2020 in the USA.

The recommended dosage is 800 mg taken orally twice daily, and Tazemetostat is also being studied for other cancers, including diffuse large B-cell lymphoma and follicular lymphoma, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tazemetostat: First Approval. Hoy, SM.[2021]

A study on the cardiotoxicity of seven anthracycline antibiotics in rats revealed significant electrocardiographic changes, including widened QRS complexes and ventricular extrasystoles, indicating potential heart damage from these drugs.

The compounds were ranked by cardiotoxicity, with adriamycin being the most toxic, and the findings correlated well with known cardiotoxic effects in humans for adriamycin, daunorubicin, and rubidazone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicologic screening of daunorubicin (NSC-82151), adriamycin (NSC-123127), and their derivatives in rats. Zbinden, G., Brändle, E.[2016]

In a phase II study involving 47 patients with various types of sarcoma, pegylated-liposomal doxorubicin (Doxil) demonstrated activity, with 3 patients achieving complete or partial responses and 15 experiencing clinical benefits despite being previously treated or unresponsive to chemotherapy.

The treatment was generally well tolerated, with mild toxicities primarily related to mucositis and hand-foot syndrome, and no significant cardiac toxicity observed, indicating a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Skubitz, KM.[2022]

Anthracyclines, particularly doxorubicin (DOX), are highly effective antitumor drugs with a broad spectrum of activity against human cancers, although they can cause significant cardiotoxicity.

While several analogs of DOX have been developed to reduce toxicity and improve administration, none have demonstrated superior antitumor efficacy compared to DOX, which remains the most effective drug in this class despite ongoing efforts to mitigate its side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anthracyclines: will we ever find a better doxorubicin? Weiss, RB.[2022]

Dexrazoxane effectively prevented left ventricular (LV) dysfunction and heart failure in children with osteosarcoma receiving high doses of doxorubicin, indicating its protective role against cardiotoxicity.

Despite preventing heart failure, dexrazoxane did not fully prevent structural changes in the heart, particularly in girls, who showed smaller heart sizes relative to body surface area, suggesting ongoing risks for cardiac stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children's Oncology Group. Kopp, LM., Womer, RB., Schwartz, CL., et al.[2022]

Aldoxorubicin, a prodrug of doxorubicin, shows improved progression-free survival and response rates in advanced sarcoma patients compared to doxorubicin, although it did not demonstrate an overall survival benefit in a Phase III study.

Aldoxorubicin has a favorable cardiotoxicity profile compared to doxorubicin, with no clinical cardiotoxicity observed in Phase I studies, suggesting it may be a safer option for patients at risk of heart damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on aldoxorubicin (INNO-206) and its potential in the treatment of soft tissue sarcomas: evidence to date. Cranmer, LD.[2020]

In a phase II study involving 16 patients with recurrent or metastatic soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no significant responses, indicating limited efficacy in this specific patient population.

Despite the lack of effectiveness, Doxil was well tolerated, with no grade 4 toxicities and only a few instances of grade 3 toxicities, suggesting a favorable safety profile for future studies in different patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. Garcia, AA., Kempf, RA., Rogers, M., et al.[2022]

The combination of pembrolizumab and doxorubicin in treating advanced soft-tissue sarcoma (STS) showed manageable toxicity, with the study meeting its primary safety endpoint and a notable incidence of hematologic adverse events, particularly neutropenia.

The treatment demonstrated promising efficacy, with an overall response rate of 36.7% and disease control in 80% of patients, alongside a median progression-free survival of 5.7 months and overall survival of 17 months, indicating potential benefits for patients with anthracycline-naive advanced STS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. Livingston, MB., Jagosky, MH., Robinson, MM., et al.[2022]

The study determined that the maximum tolerated dose (MTD) for the combination of Myocet (40 mg/m2) and ifosfamide (3000 mg/m2) is safe for patients with metastatic soft tissue sarcomas, with dose-limiting toxicity observed at a higher dose of Myocet (50 mg/m2).

Out of 10 enrolled patients, 8 received treatment, and the combination therapy was found to be feasible, leading to the recommendation for further investigation in a phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of non-pegylated liposomal doxorubicin in combination with ifosfamide in adult patients with metastatic soft tissue sarcomas. Stroppa, E., Bertuzzi, A., Di Comite, G., et al.[2021]

Dexrazoxane (DZR) effectively protects against doxorubicin (DOX)-induced cardiotoxicity in both young and mature rats, showing significant cardioprotective activity at all time points examined during the study.

The study demonstrated that DZR mitigates adverse effects on liver and kidney weights, as well as serum cholesterol and triglycerides, indicating its potential safety and efficacy in reducing the harmful side effects of DOX treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane. Della Torre, P., Mazué, G., Podestà, A., et al.[2013]

Aldoxorubicin, a derivative of doxorubicin, shows promise in treating advanced soft tissue sarcomas (STS) by releasing doxorubicin specifically in the acidic environment of tumors, potentially improving efficacy.

Preliminary phase 3 trial results indicate that aldoxorubicin has minimal cardiac toxicity compared to traditional doxorubicin and offers a progression-free survival advantage in patients with leiomyosarcoma and liposarcoma, although further studies are needed to confirm its role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldoxorubicin for the treatment of soft tissue sarcoma. Sachdev, E., Sachdev, D., Mita, M.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8247010/

Real‐world outcomes of patients with locally advanced or ... This retrospective medical records review of patients with advanced epithelioid sarcoma receiving first‐line or ≥2 lines of systemic therapies ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2020/211723Orig1s000MultidisciplineR.pdf

Multi-Discipline Review - accessdata.fda.gov The data submitted by the Applicant to support the safety and efficacy of tazemetostat in patients with epithelioid sarcoma come from Study.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8955562/

Tazemetostat: EZH2 Inhibitor - PMC Tazemetostat is a novel EZH2 inhibitor that has shown to be effective and safe with tolerable side effects in clinical trials.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.11003

Safety and efficacy of tazemetostat, a first-in-class EZH2 ... Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials.

5. tazverik.com tazverik.com/hcp/epithelioid-sarcoma/efficacy

Efficacy in Advanced Epithelioid Sarcoma Demonstrated efficacy of TAZVERIK® (tazemetostat) as first line of systemic therapy and in later lines in advanced epithelioid sarcoma patients.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02601950

NCT02601950 | A Study of Tazemetostat in Adult ... Part 1 of this trial will study the safety and the level that adverse effects of the study drug tazemetostat in combination with doxorubicin (current front ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.11563

Results of the phase 1b soft-tissue sarcoma (STS) portion ... The combination of TAZ + DOX was generally well tolerated in this dose finding study in patients with advanced STS.

8. tazverik.com tazverik.com/hcp/epithelioid-sarcoma/safety-and-tolerability

Safety & Tolerability in Advanced Epithelioid Sarcoma Serious adverse reactions in ≥3% of patients who received TAZVERIK were hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress. 1.