Clinical trial NCT05734066: Study of Lurbinectedin Monotherapy in Pediatric and Young Adult Participants With Relapsed/Refractory Ewing Sarcoma
Official title: A Phase 1/2, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), Recommended Phase 2 Dose (RP2D), and Efficacy of Lurbinectedin Monotherapy in Pediatric Participants With Previously Treated Solid Tumors Followed by Expansion to Assess Efficacy and Safety in Pediatric and Young Adult Participants With Relapsed/Refractory Ewing Sarcoma.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Refractory Ewing Sarcoma
Relapsed Ewing Sarcoma
Ewing Sarcoma
Keywords: Solid Tumors
lurbinectedin
ewing's sarcoma
soft tissue sarcoma
sarcomas
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2023-02-17
Enrollment: 60
Sex: ALL
Minimum age (years): 2
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study is conducted in two phases. The phase 1 portion of the study evaluates the safety, tolerability, pharmacokinetics (PK), recommended phase 2 dose (RP2D), and effectiveness of lurbinectedin monotherapy in pediatric participants with previously treated solid tumors. This is followed by the phase 2 portion, to further assess the effectiveness and safety in pediatric and young adult participants with recurrent/refractory Ewing sarcoma.


Eligibility criteria: Key Inclusion Criteria:

Age

* Participant must meet the following age requirements at the time the informed consent form (ICF) (and assent form, if applicable) is signed:

  * Phase 1 Part 1: participants must be ≥ 2 to \< 18 years of age.
  * Phase 1 Part 2: participants must be ≥ 2 to ≤ 30 years of age.
  * Phase 2: participants must be ≥ 2 to ≤ 30 years of age.

Type of Participant and Disease Characteristics

* Participant has a confirmed solid tumor
* The participant has a Lansky/Karnofsky performance status score of ≥ 50%.
* The participant has adequate liver function, evidenced by the following laboratory values:

  * Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN).
  * Total bilirubin ≤ 1.5 × institutional ULN (with the exception of participants with Gilbert's syndrome who must have bilirubin \< 3 × institutional ULN).
* The participant has adequate bone marrow function, evidenced by the following:

  * Absolute neutrophil count (ANC) ≥ 1.0 × 109/L (independent of growth factor support within 1 week of screening laboratories).
* Platelets ≥ 100 × 109/L (without platelet transfusion within previous 7 days of screening laboratories).

  * Hemoglobin ≥ 8 g/dL (note: may have been transfused).
* The participant has an adequate renal function:

  * Calculated creatinine clearance (use Cockcroft-Gault formula for participants ≥ 18 years; Schwartz equation for participants \< 18 years) ≥ 60 mL/min.
* The participant has an adequate cardiac function:

  * Left ventricular ejection fraction or shortening fraction per institutional norm ≥ institutional lower level of normal.
* The participant has creatine phosphokinase ≤ 2.5 × institutional ULN.

Weight

* The participant has body weight ≥ 15 kg.

Sex and Contraceptive/Barrier Requirements

Male participants:

Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 4 months after the last dose of study intervention:

* Refrain from donating sperm.

PLUS, either:

* Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.

OR

* Must agree to use contraception/barrier as detailed below:

  * Agree to use a male condom with female partner and use of an additional highly effective contraceptive method with a failure rate of \< 1% per year when having sexual intercourse with a Woman of childbearing potential (WOCBP) who is not currently pregnant.
  * Note: male participants who are azoospermic (vasectomized or due to a medical cause) are still required to follow the protocol-specified contraception/barrier criteria.

Female participants:

A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

* Is a Woman of nonchildbearing potential (WONCBP). OR
* Is a WOCBP and using an acceptable contraceptive method during the study intervention period (at least 7 months after the last dose of study intervention). The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.
* A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 7 days before the first dose of study intervention.

  * If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
* Additional requirements for pregnancy testing during and after study intervention.
* The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

Informed Consent

* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Key Exclusion Criteria:

Medical Conditions

* corrected QT interval (QTc) prolongation defined as a QTc ≥ 470 ms using the Bazett formula.
* Known symptomatic Central nervous system (CNS) metastases requiring steroids. Participants with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to enrollment, have discontinued high dose steroid treatment for these metastases for at least 2 weeks, and are neurologically stable (physiologic doses of steroids and short courses of steroids for other indications are acceptable).
* Persisting toxicity related to prior therapy; however, alopecia, sensory neuropathy, hypothyroidism, and rash Grade ≤ 2 are acceptable, and other Grade ≤ 2 adverse events (AEs) not constituting a safety risk based on the investigator's judgement are acceptable.
* An uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy, symptomatic heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Any other major illness that, in the investigator's judgment, could substantially increase the risk associated with participation in this study.
* Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high-risk for treatment complications.

Prior/Concomitant Therapy

* Received prior treatment with lurbinectedin or trabectedin.
* Received prior treatment with any investigational product within 4 weeks of first infusion of study intervention. Observational studies are permitted.
* Received live or live attenuated vaccines within 4 weeks of the first dose of study treatment or plans to receive live vaccines during study participation. Administration of inactive vaccines or messenger ribonucleic acid (mRNA) vaccines (for example, inactivated influenza vaccines or COVID-19 vaccines) are allowed.
* Had major surgery ≤ 4 weeks or radiation therapy ≤ 2 weeks prior to enrollment unless fully recovered. Prior palliative radiotherapy is permitted, provided it was completed at least 2 weeks prior to participant enrollment.
* Received prior allogeneic bone marrow transplantation or solid organ transplant.
* Received chemotherapy ≤ 3 weeks prior to start of study intervention.

Diagnostic Assessments

* Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or Polymerase chain reaction (PCR) test for HCV RNA if HCV antibody test is positive).
* Human immunodeficiency infection at screening (positive anti-HIV antibody).

Other Exclusions

* Has a known or suspected hypersensitivity to any of the components of the study intervention.
* The participant or parent(s)/guardian(s) is/are unable to comply with the study visit schedule and other protocol requirements, in the opinion of the investigator

Primary outcomes:
measure: Phase 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
timeFrame: Day -28 up to 15 months postdose.
measure: Phase 1: Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
timeFrame: Post-baseline (Day 1) up to approximately 30 months.
measure: Phase 2: Objective Response Rate (ORR) Based on Investigator Assessment (IA)
timeFrame: Day -28 up to a total of 31 months postdose.
Secondary outcomes:
measure: Phase 1: Maximum Plasma Concentration (Cmax) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 1: Plasma Trough Concentration (Ctrough) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 1: Plasma Concentration at the End of Infusion (CEOI) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 1: Area Under the Plasma Concentration-Time Curve (AUC) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 1: Clearance (CL) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 1: Volume of Distribution at Steady-State (Vss) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 1: Objective Response Rate (ORR) Based on Investigator Assessment (IA)
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 1: Progression-Free Survival (PFS) Based on Investigator Assessment (IA)
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 1: Duration of Response (DOR) in Participants with Confirmed Complete Response (CR) or Partial Response (PR)
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 1: Disease Control Rate (DCR)
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 1: Clinical Benefit Rate (CBR) With Stable Disease (SD) for At Least 12 Weeks
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 1: Overall Survival (OS)
timeFrame: Post-baseline (Day 1) up to 31 months postdose.
measure: Phase 2: Plasma Concentration of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 2: Plasma Trough Concentration (Ctrough) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 2: Plasma Concentration at the End of Infusion (CEOI) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 2: Clearance (CL) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 2: Volume of Distribution at Steady-State (Vss) of Lurbinectedin
timeFrame: Day 1: Predose up to approximately 168 hours postdose; Days 16, 31, 46: Predose up to approximately 5 minutes postdose.
measure: Phase 2: Progression-Free Survival (PFS) Based on IA
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 2: Duration of Response (DOR) in Participants with Confirmed Complete Response (CR) or Partial Response (PR)
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 2: Disease Control Rate (DCR)
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 2: Clinical Benefit Rate (CBR) With Stable Disease (SD) for At Least 12 Weeks
timeFrame: Day -28 up to a total of 31 months postdose.
measure: Phase 2: Overall Survival (OS)
timeFrame: Post-baseline (Day 1) up to 31 months postdose.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford Children's Health
state: California
city: Washington
country: United States
facility: Childrens National Hospital Michigan
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Arthur M. Blank Hospital Children's Healthcare of Atlanta
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Grand Rapids
country: United States
facility: Corewell Health
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Childrens
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern in Texas
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Jazz Pharmaceuticals
name: Jazz Study Director
role: STUDY_DIRECTOR
References: