PEN-866 + Chemotherapy for Sarcoma

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a new drug, PEN-866 (an Hsp90-targeted SN-38 conjugate), combined with vincristine and temozolomide, can more effectively treat certain cancers in adolescents and young adults. PEN-866 remains longer in tumor cells and may be more effective for Ewing sarcoma and rhabdomyosarcoma. The trial targets solid tumors that have returned after standard treatments or lack standard treatments. It is suitable for individuals aged 12-39 with these specific cancers that have not responded to previous therapies. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that PEN-866 offers potential benefits. It specifically targets tumor cells, allowing it to remain in the tumor longer and possibly reducing side effects on healthy cells. However, limited information exists about its safety in humans.

Temozolomide, a previously used drug, is generally safe but can cause side effects like nausea, vomiting, and tiredness. In rare cases, more serious side effects may occur.

Vincristine, another drug in the trial, has known side effects such as nerve pain and constipation. These are well-documented, and doctors know how to manage them.

As this trial is in its early stages, it primarily aims to assess the safety of these drugs when used together. Doctors will closely monitor participants for any side effects, ensuring careful oversight for safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about PEN-866 for sarcoma because it represents a novel approach to cancer treatment. Unlike traditional chemotherapy options such as doxorubicin or ifosfamide, which generally attack rapidly dividing cells indiscriminately, PEN-866 is a small molecule drug conjugate designed to more specifically target cancer cells. It delivers a heat shock protein 90 (Hsp90) inhibitor directly to tumor cells, potentially increasing the treatment's effectiveness while reducing harm to healthy cells. This targeted action could lead to better outcomes and fewer side effects, setting it apart from standard treatments.

What evidence suggests that this trial's treatments could be effective for sarcoma?

This trial studies PEN-866 for its ability to target cancer cells by attaching to a protein called HSP90, delivering a cancer-fighting substance directly to the tumor. Some studies have shown complete tumor shrinkage with this approach. Participants will receive PEN-866 combined with fixed doses of Temozolomide and Vincristine. Temozolomide is generally well-tolerated but has limited success on its own in treating advanced sarcoma, with patients typically experiencing no tumor growth for about 3.5 months. Vincristine has shown varying success rates, from 0 to 43%, in treating certain types of sarcoma, like rhabdomyosarcoma, and can help delay tumor growth. Combining these drugs in this trial may enhance their effectiveness, as PEN-866 remains in cancer cells longer, potentially increasing the overall treatment effect. ^{1 2 3 4 5}

Who Is on the Research Team?

Christine M Heske, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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.

I have not had major surgery in the last 28 days.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03221400

PEN-866 in Patients With Advanced Solid Malignancies PEN-866 Sodium is a miniaturized conjugate that comprises an HSP90 targeting ligand linked to SN-38, the active metabolite of irinotecan. PEN-866 is available ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0923753419586835

First in human phase I/IIa study of PEN-866, a heat shock ... PEN-866, a miniature drug conjugate with an SN-38 payload that targets and binds to the activated tumor HSP90, yielded complete tumor regressions in ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.3515

Pen-866, a miniature drug conjugate of a heat shock ... PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in ...

4. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/locnartecan

Definition of HSP90-targeted SN-38 conjugate PEN-866 Compared to SN-38 alone, PEN-866 preferentially targets, accumulates and is retained in the tumor cells due to its binding to Hsp90, which results in increased ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11260857/

An update on the status of HSP90 inhibitors in cancer clinical ... Compared to SN-38 alone, PEN-866 preferentially targets and is retained in the tumor due to its binding to HSP90. Inside the tumor cells the SN-38 moiety is ...