Tazemetostat + Doxorubicin for Sarcoma

Recruiting at 1 trial location

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

164 Participants Needed

Trial Summary

What is the purpose of this trial?

The participants of this study will have advanced epithelioid sarcoma. Sarcoma is a cancer of the connective tissues, such as nerves, muscles and bones. Epithelioid sarcoma is an ultra-rare sarcoma of the soft-tissue. Part 1 of this trial will evaluate the safety and the level of the study drug that the study drug combinations can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for the next part of the study. Part 2 will evaluate and compare for each of the study drug combinations how long participants live without their disease getting worse. The study drug is called tazemetostat. The study will test tazemetostat in combination with doxorubicin compared to placebo (dummy treatment) in combination with doxorubicin. Doxorubicin is a current front line treatment for epithelioid sarcoma

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.

What data supports the effectiveness of the drug Tazemetostat + Doxorubicin for sarcoma?

Tazemetostat has been approved for treating epithelioid sarcoma, showing promise in this type of cancer. Doxorubicin is a standard treatment for soft tissue sarcomas, although its effectiveness can vary. Combining these drugs may offer a new approach, but more research is needed to confirm their combined effectiveness for sarcoma. ^{1 2 3 4 5}

Is the combination of Tazemetostat and Doxorubicin safe for humans?

Doxorubicin, also known as Adriamycin, can cause heart-related side effects, such as changes in heart rhythm and heart failure, especially at higher doses. However, a drug called dexrazoxane can help protect against these heart issues. Liposomal forms of doxorubicin, like Caelyx, have been developed to reduce these toxic effects. ^{2 6 7 8 9}

What makes the drug Tazemetostat + Doxorubicin unique for treating sarcoma?

Tazemetostat + Doxorubicin is unique because it combines a targeted therapy (Tazemetostat) with a traditional chemotherapy drug (Doxorubicin), potentially offering a novel approach to treating sarcoma by targeting specific cancer pathways while also using a well-established chemotherapy agent. ^{1 2 4 10 11}

Research Team

Ipsen Medical Director

Principal Investigator

Ipsen

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. [2022]

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

Tazemetostat: First Approval. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Aldoxorubicin for the treatment of soft tissue sarcoma. [2019]

5. United States 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. [2021]

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

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

7. Germany pubmed.ncbi.nlm.nih.gov

Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane. [2013]

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

The anthracyclines: will we ever find a better doxorubicin? [2022]

9. England 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. [2022]

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

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. [2022]

11. England pubmed.ncbi.nlm.nih.gov

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