Gastrointestinal Malignancies
Conditions
Keywords
Gastrointestinal Malignancies, phase II
Brief summary
The purpose of this research is to evaluate the activity and safety of lurbinectedin in adult patients with advanced Gastrointestinal Malignancies with DNA repair mutations.
Interventions
Lurbinectedin will be administered with a minimum total volume of 100 mL of solution for infusion (either on 5% glucose or 0.9% sodium chloride). Lurbinectedin will be administered intravenously through peripheral or central lines at a dose of 3.2 mg/m2 at a fixed infusion rate.
Sponsors
HonorHealth Research Institute
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) at 12 Weeks | 12 weeks | The antitumor activity of lurbinectedin was measured in terms of overall response rate (ORR) at 12 weeks. ORR was defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) according to RECIST v.1.1. CR was defined as the complete radiologic disappearance of all target lesions, while PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From initiation of study treatment up to study completion, up to 20 months | Duration of response (DOR) was defined as the time from when a participant was reported to respond to lurbinectedin treatment (complete response (CR) or partial response (PR) by RECIST v1.1) to the time when they experienced progressive disease (PD) or death. CR was defined as the complete radiologic disappearance of all target lesions, PR as at least a 30% decrease in the sum of the longest diameter of target lesions, and PD as at least a 20% increase in the sum of the longest diameter of target lesions. |
| Clinical Benefit | From 4 months up to 20 months | Clinical benefit was defined as the percentage of patients with a complete response (CR), partial response (PR), or stable disease (SD), as measured by RECIST v.1.1, for ≥4 months. CR was defined as the complete radiologic disappearance of all target lesions, PR as at least a 30% decrease in the sum of the longest diameter of target lesions, and SD as no change in the sum of the longest diameter of target lesions. |
| Normalization of Tumor Markers | From initiation of study treatment until end of study treatment, up to 9.1 weeks | The number of participants with \> 2 x ULN tumor marker values at baseline who had their tumor marker values normalize to at or below ULN after receiving lurbinectedin therapy. Tumor markers included CA19-9 and CEA for non-expressors of CA 19-9. ULN was defined at 35 U/mL for CA 19-9 and 3 ng/mL for CEA. |
| Progression-free Survival (PFS) | From initiation of study treatment to disease progression/death/last tumor evaluation, up to 4.1 months | Progression-free survival (PFS) was defined as the time from the first infusion of lurbinectedin to the date of progressive disease, death (of any cause), or last tumor evaluation. |
| Progression-free Survival Rate at Three Months (PFS3) | 3 months | Progression-free survival rate at three months (PFS3) was defined as the percentage of patients who were alive and progression-free three months after the first infusion of lurbinectedin. |
| Overall Survival (OS) | From initiation of study treatment to date of death/last patient contact, up to 20 months | Overall survival (OS) was defined as the time from the first infusion of lurbinectedin to the date of death (of any cause) or last patient contact. |
| Overall Survival Rate at Six Months (OS6) | 6 months | Overall survival rate at six months (OS6) was defined as the percentage of patients who were alive six months after the first infusion of lurbinectedin. |
| Overall Survival Rate at 12 Months (OS12) | 12 months | Overall survival rate at 12 months (OS12) was defined as the percentage of patients who were alive 12 months after the first infusion of lurbinectedin. |
| Adverse Events Possibly or Definitely Related to Lurbinectedin | From initiation of study treatment to end of follow-up, up to 20 months | Adverse events (AEs) were graded and collected according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0). AEs that were determined to be possibly or definitely related to lurbinectedin are reported here. The AE grading scale for NCI-CTCAE v5.0 is as follows: Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe, non-life threatening; Grade 4 - life-threatening; Grade 5 - death. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORErkut Borazanci, MD
HonorHealth Research Institute
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.5 Years |
| DNA Repair Gene Mutation Ataxia-Telangiectasia Mutated (ATM) | 2 Participants |
| DNA Repair Gene Mutation AT-Rich Interaction Domain 1A (ARID1A) | 5 Participants |
| DNA Repair Gene Mutation Breast Cancer Gene 1 (BRCA1) | 2 Participants |
| DNA Repair Gene Mutation Checkpoint Kinase 2 (CHEK2) | 1 Participants |
| DNA Repair Gene Mutation Fanconi Anemia Complementation (FANC) | 1 Participants |
| ECOG Performance Status Score ECOG Score 0 | 1 Participants |
| ECOG Performance Status Score ECOG Score 1 | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of Prior Lines of Therapy 2 | 5 Participants |
| Number of Prior Lines of Therapy 3 | 1 Participants |
| Number of Prior Lines of Therapy 4 | 1 Participants |
| Number of Prior Lines of Therapy 5 | 1 Participants |
| Primary Cancer Type Pancreas | 7 Participants |
| Primary Cancer Type Rectum | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
| Site of Metastasis Liver | 5 Participants |
| Site of Metastasis Lung | 2 Participants |
| Site of Metastasis Peritoneum | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 7 / 8 |
Outcome results
None listed