Neoadjuvant Lurbinectedin and Preoperative Radiation for Treating Soft Tissue Sarcomas

NCT06217536 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 23872NCI-2024-00107
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a multi-center, multi-arm open-label phase Ib/II clinical study assessing the efficacy of concurrent lurbinectedin in combination with radiotherapy in patients with locally advanced, resectable, high-grade sarcomas.

Conditions

Locally Advanced Soft Tissue Sarcoma

Outcome Measures

Primary Outcomes (5)

• Proportion of participants with dose-limiting toxicities (DLTs) (Phase 1b)

  The proportion of participants with reported DLTs will be reported for

  4 weeks

• Maximum Tolerated Dose (MTD) (Phase 1b)

  MTD is defined as the highest dose at which no more than one instance of dose limiting toxicity (DLT) is observed among 1 of 6 participants treated.

  Up to 6 months

• Pathological necrosis rate (Phase 2, Cohort 1)

  Pathological necrosis rate, defined as the proportion of participants with \>=95% pathological necrosis.

  Up to 12 weeks

• Local control rate (Phase 2, Cohort 2)

  Local control rate is defined as the proportion of participants with \>=50% of the resected sample showing any histological treatment effect.

  Up to 12 weeks

• Overall response rate (Phase 2, Cohort 3)

  Overall response rate is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  Up to 12 weeks

Secondary Outcomes (5)

• Median time to disease progression (TTP)

  Up to 2 years

• Overall Response Rate (ORR)

  Up to 12 weeks

• Median Overall Survival (OS)

  Up to 2 years

• Incidence of radiation related skin toxicity

  Up to 6 months

• Proportion of participants requiring wound care

  Up to 4 months after non-investigational surgery

Study Arms (6)

Phase 1b, Cohort 1 (Extremity and Trunk Sarcoma)

EXPERIMENTAL

Participants will receive up to 3.2 mg/m\^2 of neoadjuvant lurbinectedin IV once every cycle (a cycle is 21 days) in combination with 2 weeks of pre-operative radiation given as 35 Gy in 5 fractions (gross tumor volume (GTV)) with fractions administered at least every other day starting on cycle 2 for participants with extremity and trunk sarcoma. Non-investigational surgery will take place 4-6 weeks after completion of radiation therapy. Participants with metastatic disease at the time of study enrollment may be able to continue study treatment for 2 years from the time of initiating treatment. Participants with localized disease at the time of study enrollment may continue study treatment for approximately 3 months AND then be followed on-study surveillance.

Drug: Lurbinectedin; Radiation: Radiotherapy; Procedure: Non-investigational surgery

Phase 1b, Cohort 2 (Extremity Myxoid Liposarcoma)

EXPERIMENTAL

Participants will receive up to 3.2 mg/m\^2 of neoadjuvant lurbinectedin IV once every cycle (a cycle is 21 days) in combination with 2 weeks of pre-operative radiation given as 35 Gy in 5 fractions (gross tumor volume (GTV)) with fractions administered at least every other day starting on cycle 2 for participants with extremity myxoid Liposarcoma. Non-investigational surgery will take place 4-6 weeks after completion of radiation therapy. Participants with metastatic disease at the time of study enrollment may be able to continue study treatment for 2 years from the time of initiating treatment. Participants with localized disease at the time of study enrollment may continue study treatment for approximately 3 months AND then be followed on-study surveillance.

Drug: Lurbinectedin; Radiation: Radiotherapy; Procedure: Non-investigational surgery

Phase 1b, Cohort 3: Retroperitoneal Sarcoma

EXPERIMENTAL

Participants will receive up to 3.2 mg/m\^2 of neoadjuvant lurbinectedin IV once every cycle (a cycle is 21 days) in combination with 6 weeks of pre-operative conventional external beam radiation therapy given as 45-50.4 Gy delivered over 25-28 fractions starting on cycle 1 for participants with retroperitoneal sarcoma. Non-investigational surgery will take place 4-6 weeks after completion of radiation therapy. Participants with metastatic disease at the time of study enrollment may be able to continue study treatment for 2 years from the time of initiating treatment. Participants with localized disease at the time of study enrollment may continue study treatment for approximately 3 months AND then be followed on-study surveillance.

Drug: Lurbinectedin; Radiation: Radiotherapy; Procedure: Non-investigational surgery

Phase 2, Cohort 1: Extremity and trunk sarcoma

EXPERIMENTAL

Participants will receive the maximum tolerated dose of neoadjuvant lurbinectedin IV once every cycle (a cycle is 21 days) in combination with 2 weeks of pre-operative radiation given as 35 Gy in 5 fractions (gross tumor volume (GTV)) with fractions administered at least every other day starting on cycle 2 for participants with extremity and trunk sarcoma. Non-investigational surgery will take place 4-6 weeks after completion of radiation therapy. Participants with metastatic disease at the time of study enrollment may be able to continue study treatment for 2 years from the time of initiating treatment. Participants with localized disease at the time of study enrollment may continue study treatment for approximately 3 months AND then be followed on-study surveillance.

Drug: Lurbinectedin; Radiation: Radiotherapy; Procedure: Non-investigational surgery

Phase 2, Cohort 2: Extremity myxoid liposarcoma

EXPERIMENTAL

Participants will receive the maximum tolerated dose of neoadjuvant lurbinectedin IV once every cycle (a cycle is 21 days) in combination with 2 weeks of pre-operative radiation given as 35 Gy in 5 fractions (gross tumor volume (GTV)) with fractions administered at least every other day starting on cycle 2 for participants with extremity myxoid Liposarcoma. Non-investigational surgery will take place 4-6 weeks after completion of radiation therapy. Participants with metastatic disease at the time of study enrollment may be able to continue study treatment for 2 years from the time of initiating treatment. Participants with localized disease at the time of study enrollment may continue study treatment for approximately 3 months AND then be followed on-study surveillance.

Drug: Lurbinectedin; Radiation: Radiotherapy; Procedure: Non-investigational surgery

Phase 2, Cohort 3: Retroperitoneal sarcoma

EXPERIMENTAL

Participants will receive the maximum tolerated dose of neoadjuvant lurbinectedin IV once every cycle (a cycle is 21 days) in combination with 6 weeks of pre-operative conventional external beam radiation therapy given as 45-50.4 Gy delivered over 25-28 fractions starting on cycle 1 for participants with retroperitoneal sarcoma. Non-investigational surgery will take place 4-6 weeks after completion of radiation therapy. Participants with metastatic disease at the time of study enrollment may be able to continue study treatment for 2 years from the time of initiating treatment. Participants with localized disease at the time of study enrollment may continue study treatment for approximately 3 months AND then be followed on-study surveillance.

Drug: Lurbinectedin; Radiation: Radiotherapy; Procedure: Non-investigational surgery

Interventions

Lurbinectedin DRUG

Given intravenously (IV)

Also known as: Zepzelca

Phase 1b, Cohort 1 (Extremity and Trunk Sarcoma); Phase 1b, Cohort 2 (Extremity Myxoid Liposarcoma); Phase 1b, Cohort 3: Retroperitoneal Sarcoma; Phase 2, Cohort 1: Extremity and trunk sarcoma; Phase 2, Cohort 2: Extremity myxoid liposarcoma; Phase 2, Cohort 3: Retroperitoneal sarcoma

Radiotherapy RADIATION

Conventionally fractionated radiotherapy or external beam radiation

Also known as: Radiation therapy

Phase 1b, Cohort 1 (Extremity and Trunk Sarcoma); Phase 1b, Cohort 2 (Extremity Myxoid Liposarcoma); Phase 1b, Cohort 3: Retroperitoneal Sarcoma; Phase 2, Cohort 1: Extremity and trunk sarcoma; Phase 2, Cohort 2: Extremity myxoid liposarcoma; Phase 2, Cohort 3: Retroperitoneal sarcoma

Non-investigational surgery PROCEDURE

Non-investigational surgical procedure on tumor tissue

Phase 1b, Cohort 1 (Extremity and Trunk Sarcoma); Phase 1b, Cohort 2 (Extremity Myxoid Liposarcoma); Phase 1b, Cohort 3: Retroperitoneal Sarcoma; Phase 2, Cohort 1: Extremity and trunk sarcoma; Phase 2, Cohort 2: Extremity myxoid liposarcoma; Phase 2, Cohort 3: Retroperitoneal sarcoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must have histologically or cytologically confirmed diagnosis of locally advanced soft tissue sarcoma of extremity, trunk or retroperitoneum that is resectable and for which preoperative radiotherapy is considered appropriate.
• Including metastatic (stage IV) disease for which radiotherapy and surgical resection of the primary tumor are indicated.
• Grade 1 myxoid liposarcoma can be included if preoperative radiotherapy is considered appropriate.
• For all other sarcomas, only grade 2 or 3 will be included.
• Must have measurable disease defined as a tumor size at least \>= 5 cm in the longest diameter as measured by Computerized tomography (CT) scan or Magnetic resonance imaging (MRI) for which radiation is feasible and indicated.
• Age \>=18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status \<= 1 (Karnofsky ≥ 70%).
• Demonstrates adequate organ function within 21 days of Day 1 as defined below:
• Hemoglobin \>= 9.0 g / dL.
• prothrombin time (PT) (or International Normalized Ratio (INR)) and partial thromboplastin time (PTT) (or activated partial thromboplastin time (aPTT)) \<1.5 x upper limit of normal (ULN).
• Absolute neutrophil count \>=1,500/microliter (mcL).
• Platelets \>=100,000/mcL.
• Total bilirubin within normal institutional limits, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT)\<=3 X institutional upper limit of normal.
• Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) \<=3 X institutional upper limit of normal.

You may not qualify if:

• Has the following histologic subtypes: gastrointestinal stromal tumor (GIST), desmoid, Ewing sarcoma, bone sarcomas, Kaposi sarcoma.
• Prior history of trabectedin or lurbinectedin treatment.
• Prior radiation therapy in excess of 20 Gray (Gy) conventionally fractionated radiotherapy (RT) to the site of the current diagnosis of sarcoma. No overlap with prior radiation fields in excess of 20 Gy is allowed.
• Currently receiving treatment in another invasive investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s).
• Known central nervous system (CNS) disease, except for treated brain metastasis: Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS); Gamma Knife, linear particle accelerator (LINAC), or equivalent) or a combination as deemed appropriate by the treating physician. Participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lurbinectedin.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Participants on strong or moderate cytochrome P450 (CYP)3A inducers or inhibitors and cannot be substituted for other drugs.
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this study.
• Has received systemic anti-cancer therapies within 3 weeks of first dose, radiation within 2 weeks, or antibody therapy within 4 weeks. Concomitant administration of Luteinizing hormone-releasing hormone (LHRH) analogues for prostate cancer and somatostatin analogues for neuroendocrine tumors are allowed as per standard of care.
• Has not recovered from adverse events due to prior anti-cancer therapy to \<= grade 1 or baseline (other than alopecia).
• Is currently receiving any other investigational agents.
• Any concurrent illness in the opinion of the investigator would affect treatment compliance.
• Participants needing concurrent antiemetic aprepitant or any other Neurokinin 1 (NK1) antagonist or related Substance P-antagonists (except rolapitant).
• Pregnant participants are excluded from this study because lurbinectedin has the potential for teratogenic or abortifacient effects. Females of childbearing potential (definition as above) must undergo a urine pregnancy test per institutional guidelines within 7 days prior to Day 1 of study treatment. Participants with a positive urine pregnancy test are excluded.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Jazz Pharmaceuticals: collaborator

MeSH Terms

Interventions

PM 01183; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Varun Monga, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 11, 2024
• First Posted: January 22, 2024
• Study Start: October 31, 2024
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): October 31, 2027
• Last Updated: November 18, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share