PEN-866 + Chemotherapy for Sarcoma

Recruiting at 1 trial location

Overseen By Jo H Hurtt, R.N.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: UGT1A1 inhibitors

Disqualifiers: Pregnancy, Uncontrolled hypertension, others

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 54 weeks

64 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: The drug PEN-866 can remain in tumor cells longer than it does in normal cells. It also may be more effective than other drugs at treating Ewing sarcoma and rhabdomyosarcoma. Researchers want to learn if combining PEN-866 with other drugs can treat certain cancers in adolescents and young adults. Objective: To learn if the combination of PEN-866 with vincristine and temozolomide can be used to treat adolescents and young adults with solid tumors that have returned after or did not respond to standard treatments, or for which there are no standard treatments. Eligibility: People ages 12-39 years who have solid tumors, Ewing sarcoma, or rhabdomyosarcoma that returned after or did not respond to standard treatments. Design: Participants will be screened with a medical history, physical exam, and eye exam. They will have heart function tests. They may have imaging scans of the chest, abdomen, and pelvis. They will give blood and urine samples. They may have a tumor biopsy. Some samples will be used for genetic testing. Some screening tests will be repeated during the study. Participants will get 3 drugs for up to 18 cycles. Each cycle lasts 21 days. They will get PEN-866 and vincristine by IV infusion (a tube in their vein) on Days 1 and 8 of each cycle. They will take temozolomide by mouth on Days 1-5 of each cycle. Participants will complete questionnaires about their physical, mental, and social health. Participants will have a follow-up visit 30 days after treatment ends. They may be contacted by phone or email for the rest of their life.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on medications that inhibit UGT1A1 or are substrates of certain enzymes and transporters, you will need to stop them at least 2 weeks or 5 half-lives before starting the trial.

What data supports the effectiveness of the drug PEN-866 + Chemotherapy for Sarcoma?

Research shows that a similar drug, STA-8666, which also targets HSP90 to deliver SN-38, caused significant tumor shrinkage and prolonged remission in mouse models of pediatric sarcoma. Additionally, the combination of temozolomide and irinotecan, components of the treatment, has shown activity in Ewing sarcoma, suggesting potential effectiveness. ^{1 2 3 4 5}

Is PEN-866 safe for humans?

The research on STA-8666, a similar drug to PEN-866, shows it has been tested in mice and demonstrated promising results in targeting tumors with fewer side effects compared to traditional treatments. However, specific safety data for humans is not provided in the available studies. ^{4 6 7 8 9}

What makes the drug PEN-866 unique for treating sarcoma?

PEN-866 is unique because it uses an HSP90 inhibitor to deliver SN-38, a topoisomerase 1 inhibitor, directly to tumor cells, enhancing its effectiveness and reducing side effects compared to traditional irinotecan treatments. This targeted delivery method allows for more persistent inhibition of tumor growth and prolonged DNA damage, potentially leading to better outcomes in sarcoma patients. ^{2 4 9 10 11}

Research Team

Christine M Heske, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adolescents and young adults aged 12-39 with solid tumors, Ewing sarcoma, or rhabdomyosarcoma that have not responded to standard treatments are eligible. They must have adequate organ function, no severe prior treatment toxicity unresolved, and agree to use contraception if applicable. Those with certain genetic conditions or on prohibited medications cannot join.

Inclusion Criteria

Histologic confirmation of original diagnosis or relapse by Laboratory of Pathology, NCI or participating site's Pathology Department

I have confirmed recurrent or refractory Ewing sarcoma or rhabdomyosarcoma.

I have had multiple treatments for my condition.

Exclusion Criteria

I am not taking any medications that interfere with specific body enzymes or transporters.

You are currently pregnant or breastfeeding.

My cancer has spread to my bone marrow, affecting my blood counts.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PEN-866, vincristine, and temozolomide for up to 18 cycles, each lasting 21 days

Up to 54 weeks

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person), ongoing contact by phone or email

Open-label extension (optional)

Participants may be contacted for the rest of their life for long-term follow-up

Treatment Details

Interventions

• PEN-866
• Temozolomide
• Vincristine

Trial Overview The trial tests a combination of PEN-866 with vincristine and temozolomide in patients who've had relapsed or refractory solid tumors. Over up to 18 cycles (21 days each), participants receive these drugs intravenously and orally while their health is monitored through exams, questionnaires, and lifelong follow-ups.

Participant Groups

Group I: 2/MTD/RP2D Experimental Treatment 3 Interventions

PEN-866 at the MTD or RP2D from phase 1 plus vincristine and temozolomide

Group II: 1/Dose Escalation Experimental Treatment 3 Interventions

Dose escalation of PEN-866 along with fixed doses of vincristine and temozolomide

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 51 patients with recurrent Ewing sarcoma, the combination of temozolomide and irinotecan (TEMIRI) demonstrated a disease control rate of 71%, indicating significant efficacy in managing this cancer.

Factors such as the Eastern Cooperative Oncology Group (ECOG) performance status and lactate dehydrogenase (LDH) levels were found to significantly influence progression-free survival, highlighting their potential as predictive markers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. Palmerini, E., Jones, RL., Setola, E., et al.[2018]

Targeted therapies combined with doxorubicin showed significant effectiveness against small cell sarcoma cell lines, with dual combinations of vorinostat and 17-DMAG achieving synergistic effects that enhanced cell killing by 60% compared to doxorubicin alone.

The study found that while vorinostat and 17-DMAG synergized with doxorubicin, sorafenib did not, and the combination of all three agents did not show synergy but increased apoptosis, indicating potential for improved treatment strategies in advanced sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted polytherapy in small cell sarcoma and its association with doxorubicin. Dumont, SN., Yang, D., Dumont, AG., et al.[2021]

The protracted d × 5×2 schedule of vincristine, irinotecan, and temozolomide (VIT) demonstrated a significantly higher objective response rate (54.5%) compared to the shorter d × 5 schedule (20.8%) in patients with relapsed or refractory Ewing sarcoma, based on a study of 46 patients.

Patients on the d × 5 schedule experienced more severe adverse events, indicating that the d × 5×2 schedule not only provided better efficacy but also had a more favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. Xu, J., Xie, L., Sun, X., et al.[2023]

STA-8666, a novel drug conjugate, shows superior antitumor efficacy and survival benefits in mouse models of Ewing sarcoma and rhabdomyosarcoma compared to conventional irinotecan, particularly in irinotecan-resistant cases.

The study indicates that STA-8666 leads to more effective and sustained inhibition of topoisomerase 1 and greater DNA damage in tumors, suggesting it may be a promising treatment option for pediatric-type sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma. Heske, CM., Mendoza, A., Edessa, LD., et al.[2019]

A combination of temozolomide and irinotecan was found to be tolerable and active in treating advanced Ewing sarcoma, with 1 complete response and 3 partial responses observed among 14 evaluable patients.

The treatment regimen was manageable, with minimal myelosuppression and only 11% of courses experiencing grade 3-4 diarrhea, suggesting that home administration of irinotecan is safe and feasible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Wagner, LM., McAllister, N., Goldsby, RE., et al.[2018]

The HSP90 inhibitor-drug conjugate STA-12-8666 effectively targets tumors by utilizing the high-affinity binding of the HSP90 inhibitor to enhance drug accumulation within cancer cells, leading to improved therapeutic outcomes.

In preclinical models, STA-12-8666 demonstrated a broad therapeutic window and sustained antitumor effects, indicating its potential as a novel anticancer treatment with reduced systemic toxicity compared to conventional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HSP90 Inhibitor-SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors. Proia, DA., Smith, DL., Zhang, J., et al.[2020]

The novel camptothecan conjugate MEN4901/T-0128 showed high antimetastatic activity in a mouse model of human colon cancer, significantly reducing lymph node metastasis compared to irinotecan and untreated controls.

In the study, only 1 out of 12 mice treated with MEN4901/T-0128 developed lymph node metastasis, while 19 out of 20 in the control group did, highlighting its potential as an effective treatment for preventing cancer spread.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate. Ma, H., Li, X., Yang, Z., et al.[2021]

EZN-2208, a pegylated form of the active metabolite of irinotecan, was well tolerated in patients with advanced colorectal cancer who had previously received standard treatments, showing promising safety profiles.

In patients with KRAS wild-type tumors, EZN-2208 combined with cetuximab resulted in a 10.7% overall response rate and a progression-free survival of 4.9 months, which was comparable to the irinotecan plus cetuximab group, indicating similar efficacy between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Garrett, CR., Bekaii-Saab, TS., Ryan, T., et al.[2021]

A phase I trial involving 41 pediatric patients with recurrent or refractory solid tumors showed that the combination of talazoparib and irinotecan, with or without temozolomide, is feasible and has demonstrated activity, particularly in Ewing sarcoma, with objective response rates of 10.3% for arm A and 25% for arm B.

The most common severe side effects included neutropenia and thrombocytopenia, indicating that while the treatment is active, it also carries significant hematologic risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. Federico, SM., Pappo, AS., Sahr, N., et al.[2021]

Bone and soft tissue sarcomas are resistant to conventional chemotherapy, but new drugs like taxanes and gemcitabine have shown efficacy, particularly in Ewing's sarcoma, which responds well to chemotherapy.

Recent research highlights the potential of targeted therapies against specific molecular markers and cancer stem cells in sarcomas, with ongoing clinical evaluations of tyrosine kinase inhibitors and other novel agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting sarcomas: therapeutic targets and their rational. Ordóñez, JL., Martins, AS., Osuna, D., et al.[2019]

Doxorubicin and ifosfamide are the primary chemotherapy drugs used for treating sarcomas, while dacarbazine has limited effectiveness, highlighting the need for improved drug combinations.

New chemotherapy agents like gemcitabine and ET-743 have shown promise in certain sarcoma sub-types, and targeted therapies along with antiangiogenic treatments are beginning to demonstrate positive results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. Fayette, J., Blay, JY.[2006]

References

1. England pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. [2018]

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

Targeted polytherapy in small cell sarcoma and its association with doxorubicin. [2021]

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

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. [2023]

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

STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma. [2019]

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

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. [2018]

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

HSP90 Inhibitor-SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors. [2020]

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

High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate. [2021]

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

Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. [2021]

9. England pubmed.ncbi.nlm.nih.gov

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. [2021]

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

Targeting sarcomas: therapeutic targets and their rational. [2019]

11. France pubmed.ncbi.nlm.nih.gov

[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. [2006]