Navtemadlin + Radiation for Soft Tissue Sarcoma

No longer recruiting at 60 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Warfarin, Factor Xa inhibitors

Disqualifiers: Pregnancy, Cardiac conditions, Metastatic disease, others

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

Compensation: Varies

Number of Visits: 3

Duration: 10-13 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety of using navtemadlin (KRT-232) with radiation therapy to treat soft tissue sarcoma, a type of cancer. Navtemadlin may hinder cancer cell growth by blocking certain enzymes, while radiation therapy uses powerful x-rays to kill cancer cells. Combining these treatments before surgery could shrink tumors, making surgery less invasive. This trial may suit individuals with intermediate or high-grade soft tissue sarcoma, with tumors larger than 5 centimeters, seeking curative treatment options. 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.

Do I need to stop taking my current medications for the trial?

The trial requires participants to stop using herbal medicines and certain medications that affect liver enzymes (CYP3A4 and CYP2C8 substrates) within 10-14 days before starting the trial and during the first 5 weeks of treatment. You will need to provide a list of medications you are taking to the trial team.

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

Research has shown that navtemadlin, when combined with radiation therapy, is generally safe for patients with soft tissue sarcoma. One study found that this combination can be administered safely before surgery. Some side effects occurred, but they were manageable. Radiation therapy is usually safe, though it can sometimes cause skin reactions or affect wound healing. Overall, these early findings suggest that using navtemadlin with radiation therapy is safe for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about navtemadlin combined with radiation therapy for soft tissue sarcoma because it targets the p53 protein, a crucial player in cell cycle regulation and tumor suppression. Unlike traditional treatments that primarily focus on surgery and chemotherapy, this approach aims to exploit the tumor's genetic vulnerabilities by using navtemadlin to inhibit MDM2, which can reactivate p53's tumor-suppressing functions. This targeted mechanism provides a novel way to tackle the cancer cells more directly, potentially improving treatment outcomes and offering hope for more effective management of soft tissue sarcoma.

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

Research has shown that navtemadlin can stop cancer cells from growing by blocking essential enzymes. In this trial, some participants will receive navtemadlin combined with radiation therapy, which studies have found patients with soft tissue sarcoma tolerate well. This treatment targets a type of soft tissue sarcoma often found in the arms, legs, or body wall. Early trials suggested that using navtemadlin with radiation before surgery might shrink tumors, making surgery easier and possibly more effective. While more research is needed, these early results are promising for people with soft tissue sarcoma. ^{1 2 3 4 5}

Who Is on the Research Team?

Meng X Welliver

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for adults with intermediate or high-grade soft tissue sarcoma larger than 5 cm, aiming for curative treatment. Participants must have no history of other cancers (with some exceptions), not be pregnant or breastfeeding, and cannot have metastatic disease. They should not have had chemotherapy or radiotherapy for the sarcoma before and must agree to avoid certain medications during the trial.

Inclusion Criteria

My treatment goal is to cure my disease.

I am scheduled for surgery to remove my primary tumor and can care for myself with minimal assistance.

I can provide samples of my tumor for testing.

Exclusion Criteria

I've had radiation in the same area where my current cancer is located.

I have not needed IV antibiotics for an infection in the last 2 weeks.

I cannot take pills due to my GI condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive navtemadlin and undergo radiation therapy for 5 weeks, followed by surgery 5-8 weeks after RT completion

10-13 weeks

Daily visits for radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

2.5 years

Every 3 months for 2 years, then at 2.5 years

What Are the Treatments Tested in This Trial?

Interventions

• KRT-232
• Navtemadlin
• Radiation Therapy

Trial Overview The study tests navtemadlin combined with radiation therapy in patients with soft tissue sarcoma. Navtemadlin blocks enzymes that cancer cells need to grow, while radiation aims to kill tumor cells. The goal is to shrink tumors before surgery.

How Is the Trial Designed?

Group I: Step 2, Group II (radiation therapy, surgery) Experimental Treatment 2 Interventions

Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.

Group II: Step 2, Group I (navtemadlin, radiation therapy, surgery) Experimental Treatment 3 Interventions

Starting with week 2, patients receive navtemadlin as in Step 1 and undergo RT daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.

Group III: Step 1 (tumor tissue testing, navtemadlin) Experimental Treatment 2 Interventions

Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-4, days 2-5, or days 1-5 of weeks 1 to 5 in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

In a phase II study involving 52 patients with high-risk primary soft tissue sarcoma, a 5-day neoadjuvant radiotherapy regimen resulted in a low rate of grade ≥2 late radiation toxicity (16%) and a 32% incidence of major wound complications.

The study identified a potential germline biomarker that could predict major wound complications, which may help improve the safety and effectiveness of radiotherapy in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Trial of 5-Day Neoadjuvant Radiotherapy for Patients with High-Risk Primary Soft Tissue Sarcoma. Kalbasi, A., Kamrava, M., Chu, FI., et al.[2021]

In a study of 59 patients with extremity soft tissue sarcomas, intensity-modulated radiotherapy (IMRT) resulted in late toxicities in 75% of patients, with the majority being mild to moderate (G1-2), including functional limitations and chronic pain.

A larger volume of healthy soft tissue surrounding the treatment area (greater than 3500 cm³) was associated with reduced late toxicities, suggesting that careful planning of radiotherapy can help minimize side effects for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective evaluation of intensity-modulated radiotherapy toxicity in extremity soft tissue sarcomas patients: A role for irradiated healthy soft tissue volume? Bourdais, R., Achkar, S., Honoré, C., et al.[2022]

Postoperative intensity-modulated radiation therapy (IMRT) for patients with soft tissue sarcomas (STSs) in the extremities and trunk wall resulted in an impressive 5-year local control rate of 88.1%, especially for patients with negative surgical margins (90% local control) compared to those with positive margins (64.8%).

The treatment demonstrated low toxicity, with only 17.6% of patients experiencing edema and 9.8% experiencing joint stiffness, indicating that IMRT is a safe and effective option for managing STSs post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative intensity-modulated radiation therapy provides favorable local control and low toxicities in patients with soft tissue sarcomas in the extremities and trunk wall. Wang, J., Wang, S., Song, Y., et al.[2020]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.11521

NRG-DT001 phase Ib trial of neoadjuvant navtemadlin ... This report contains the results for cohort A. Methods: Eligible pts had grade 2-3 STS ≥ 5 cm, age ≥ 18, and Zubrod performance status 0-1. Dose ...

2. withpower.com withpower.com/trial/phase-1-sarcoma-10-2017-7613a

Navtemadlin + Radiation for Soft Tissue Sarcoma This trial studies the effects of navtemadlin and radiation therapy in patients with soft tissue sarcoma. Navtemadlin helps stop cancer cells from growing, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7211202/

Phase 1 study of the MDM2 inhibitor AMG 232 in patients with ... Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and ...

4. researchgate.net researchgate.net/publication/367696763_NRG-DT001_phase_Ib_trial_of_neoadjuvant_navtemadlin_previously_AMG232_and_KRT232_concurrent_with_preoperative_radiotherapy_in_wild-type_p53_soft_tissue_sarcoma_of_the_extremity_and_body_wall

NRG-DT001 phase Ib trial of neoadjuvant navtemadlin ... Conclusions: Neoadjuvant navtemadlin concurrent with standard dose preoperative RT is well tolerated in patients with WT p53 STS at extremity or ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03217266

Navtemadlin and Radiation Therapy in Treating Patients ... This phase Ib trial studies the side effects of navtemadlin and radiation therapy in treating patients with soft tissue sarcoma. Navtemadlin may stop the ...