Using lurbinectedin for advanced gastrointestinal cancers with DNA repair mutations

A Phase II Pilot Clinical Trial of Lurbinectedin (Zepzelca™ PM01183) in Patients With Gastrointestinal Malignancies With DNA Repair Mutations

This study is testing if a chemotherapy drug called lurbinectedin can help adults with advanced gastrointestinal cancers that have certain DNA repair mutations feel better when other treatments haven't worked.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 19 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: HonorHealth Research Institute (Academic / other)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Scottsdale, Arizona)
• Trial ID: NCT05229588 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness and safety of lurbinectedin, a chemotherapy drug, in adult patients suffering from advanced gastrointestinal malignancies that have specific DNA repair mutations. Participants must have confirmed diagnoses of gastrointestinal carcinoma that is locally advanced or metastatic and have shown disease progression despite prior treatments. The study aims to determine how well lurbinectedin works in this specific patient population and to monitor any associated side effects.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with advanced gastrointestinal malignancies and specific DNA repair mutations.

Not a fit: Patients without DNA repair mutations or those with early-stage gastrointestinal cancers may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced gastrointestinal cancers that have limited treatment alternatives.

How similar studies have performed: While there have been studies on lurbinectedin for other cancers, this specific application in gastrointestinal malignancies with DNA repair mutations is relatively novel.

Eligibility criteria

Inclusion Criteria:

* Voluntary written informed consent form (ICF) of the patient obtained before any study-specific procedure.
* Age ≥ 18 years of age; male or female.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤1
* Histologically or cytologically confirmed gastrointestinal carcinoma
* Locally advanced unresectable or metastatic disease at study entry
* Known deleterious or suspected deleterious (or equivalent interpretation) mutations in DNA repair in ATM, ATR, CHEK2, BRCA1, BRCA2, RAD51, BRIP1, PALB2, PTEN, FANC, NBN, EMSY, MRE11, or ARID1A prior to study entry
* Progressive disease to prior treatment. Patients no longer able to continue prior treatment due to intolerable toxicity may be considered for study participation provided that radiology assessment confirms either stable disease or disease progression (i.e., no response to treatment).
* Measurable tumor lesions according to RECIST 1.1 criteria.
* Adequate hematological, renal, metabolic and hepatic function, defined as:

  1. Hemoglobin ≥9 g/dL (patients may have received prior red blood cell \[RBC\] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥1.5 x 109/L, and platelet count ≥100 x 109/L.
  2. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3.0 x upper limit of normal (ULN).
  3. Total bilirubin ≤ ULN.
  4. Albumin ≥3.0 g/dL.
  5. Calculated creatinine clearance (CrCL) ≥30 mL/min (according to the Cockcroft and Gault´s formula).
* 11. Washout periods prior to Day 1 of Cycle 1:

  1. At least three weeks since last prior chemotherapy and/or investigational drugs.
  2. At least four weeks since the last radiotherapy (RT) \> 30 Gy.
  3. At least two weeks since the last palliative RT (≤ 10 fractions or ≤ 30 Gy total dose).
* Patients with prior malignancy successfully treated who are currently stable and on no active treatment are eligible.
* Recovery to grade ≤1 from any adverse event (AE) derived from previous anticancer treatment (excluding alopecia and/or skin toxicity of any grade and grade ≤2 peripheral neuropathy) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.5).
* Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure\* during the trial and up to six weeks after treatment discontinuation, and fertile male patients with WOCBP partners must agree to refrain from fathering a child or donating sperm during the trial and up to four months after treatment discontinuation.

  * Highly effective methods: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence

Exclusion Criteria:

* Prior treatment with lurbinectedin or trabectedin
* Neuroendocrine differentiation subtype in histology
* More than three prior systemic chemotherapy lines for advanced disease
* Known brain metastases or leptomeningeal disease involvement
* Concomitant diseases/conditions:

  1. History of cardiac disease: myocardial infarction or symptomatic/uncontrolled angina within the year prior to enrollment; or pain history of left ventricular ejection fraction (LVEF) ≤ 50% assessed by multiple-gated acquisition scan (MUGA) or equivalent by ultrasound (US); or symptomatic arrhythmia.
  2. Generalized edema, and/or ascites clinically evident or requiring drainages within three weeks prior to study entry. Permanent external drainages due to ascites are also excluded.
  3. Immunocompromised patients, including those known to be infected by human immunodeficiency virus (HIV).
  4. Known chronically active hepatitis B virus (HBV) or hepatitis C virus (HCV). For hepatitis B, this includes positive tests for both hepatitis B surface antigen and quantitative hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both hepatitis C antibody and quantitative hepatitis C PCR.
  5. Active uncontrolled infection.
  6. Limitation of the patient's ability to comply with the treatment or to follow-up the protocol.
  7. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
* Patients acutely ill and/or in immediate vital distress, including those with rapidly deteriorating clinical condition or who may require unscheduled hospitalizations due to uncontrolled disease symptoms within the prior two weeks to treatment registration.
* Pregnant or breastfeeding women.
* Live vaccine administration within 3 weeks of study entry

Where this trial is running

Scottsdale, Arizona

• HonorHealth Research Institute — Scottsdale, Arizona, United States (Recruiting)

Study contacts

• Principal investigator: Erkut Borazanci, MD — HonorHealth Research Institute
• Study coordinator: Erkut Borazanci, MD

Conditions Gastrointestinal Malignancies; phase II