Solid Tumor, Adult
Conditions
Keywords
Durvalumab, Trabectedin, Maximum Tolerated Dose, Lung Cancer, Sarcoma
Brief summary
A phase 1 study examining the combination of Durvalumab (MEDI4736) and Trabectedin in various solid tumor types. The study seeks to determine a safe dose of the combination of study drugs and then examine this dose in larger groups of patients of specific tumor types to evaluate its anti-tumor efficacy. Treatment will continue in patients who respond for up to 1 year.
Detailed description
This study will include dose escalation and dose expansion phases. In the dose escalation portion, patients with advanced cancer will be enrolled and treated with Durvalumab and Trabectedin. Durvalumab will be administered at the same dose in each dose escalation cohort, while the dose of Trabectedin will be progressively increased in different cohorts until the safest dose of the combination is determined. In the dose expansion portion patients will be treated with the safest dose of the study drugs determined during the dose escalation phase. There will be two separate groups of patients treated at this dose to evaluate anti-tumor efficacy of the combination. One group will consist of non-small-cell lung cancer patients previously treated with PD-1 or PD-L1 inhibitors and another group will consist of an immunotherapy naive group of patients. This immunotherapy naive group of patients will include sarcoma and another tumor type, this other tumor type will be determined based on anti-tumor efficacy seen during the dose escalation. The study drugs will be given intravenously every 3 weeks. Treatment will continue for up to one year or until disease progression.
Interventions
DRUGDose Escalation of Durvalumab and Trabectedin
There will be a fixed dosage of Durvalumab, 1125mg, given intravenously over 60 minutes on Day 2 every 21 days. There will be an increase in Trabectedin for each cohort, given through intravenous infusion over a 24 hour period on Day 1 every 21 days as an outpatient. * Cohort -1: Durvalumab 1125mg with Trabectedin 0.5mg/m2 * Cohort 1: Durvalumab 1125mg with Trabectedin 0.75mg/m2 * Cohort 2: Durvalumab 1125mg with Trabectedin 1.0mg/m2 * Cohort 3: Durvalumab 1125mg with Trabectedin 1.2mg/m2 * Cohort 4: Durvalumab 1125mg with Trabectedin 1.5mg/m2
DRUGDose Expansion of Durvalumab and Trabectedin
There will be a fixed dosage of Durvalumab, 1125mg, given intravenously over 60 minutes on Day 2 every 21 days. There will be a fixed dosage of Trabectedin for each cohort, whatever was determined to be the safest dose during the Dose Escalation Phase, and it will be given through intravenous infusion over a 24 hour period on Day 1 every 21 days as an outpatient.
Sponsors
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
at Screening and C1D1: 1. Ability to understand and the willingness to sign a written informed consent document 2. Written informed consent and any locally-required authorization (e.g., HIPAA in the USA) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations 3. AGE ≥ 18 4. Alkaline phosphatase (ALP) level ≤ upper limit of normal (ULN) 5. Aspartate aminotransferase (AST) and alanine amino transferase (ALT) ≤ ULN 6. Bilirubin ≤ ULN, if total bilirubin is \> ULN, measure direct/indirect bilirubin to evaluate for Gilbert's Syndrome (if direct bilirubin is within normal range, subject may be eligible) 7. Albumin ≥ 2.5 g/dL 8. CPK ≤ 2.5 xULN 9. Body weight \> 30 kg 10. ECOG performance status 0-1 11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 12. Evaluable disease for dose escalation, measurable disease per RECIST 1.1 for dose expansions 13. Hemoglobin ≥ 9 g/dL 14. Neutrophil count ≥ 1.5 x 10\^9/L 15. Platelets ≥ 100 x 10\^9/L 16. Measured creatinine clearance (CL) ≥ 50 mL/min or Calculated creatinine CL≥ 50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: This calculation will be performed by a member of the clinical study team Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = \[Weight (kg) x (140 - Age)/72 x serum creatinine (mg/dL)\] x 0.85 17. Any advanced unresectable/stage IV solid tumor with exception of primary CNS malignancy is permitted. 18. Enrolled patients may be candidates for standard of care therapy with trabectedin or second line/subsequent line treatment for advanced disease with PD-1/PD-L1 inhibitor monotherapy. Otherwise they should have no standard of care option available or be felt appropriate for a phase I clinical trial in the opinion of the treating investigator. Prior PD-1/PD-L1 exposure is not an
Exclusion criteria
. 19. For the expansion cohort of NSCLC patients previously treated with and having progressed on immunotherapy patients must have no standard of care option available or have contraindications to such treatment (including those who decline such treatment). 20. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and exams including follow up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dosage of the Durvalumab and Trabectedin Combination | Up to 1 year on study treatment plus 90 days safety follow-up, up to 15 months | Recommended Phase II Dose (RP2D) is the dose determined safest for further evaluation based on both early and late onset side effects detected during the dose escalation phase. |
| Maximum tolerated dose | First 2 cycles at 21 days each, equal to 42 days. | Maximum Tolerated Dose (MTD) is defined as the highest dose level with no more than 1 Dose Limiting Toxicity (DLT) reported out of up to 6 DLT-evaluable subjects determined during the dose escalation phase |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) of the Durvalumab and Trabectedin Combination | After 2 cycles of study drugs to study end date, up to 24 months. | Determined by complete response, partial response, or stable disease. |
| One Year Progression Free Survival (PFS) of the Durvalumab and Trabectedin Combination | Study start date to progression, or death, whichever comes first, up to 24 months. | PFS is determined by RECIST v1.1 and iRECIST |
| Overall Response Rate (ORR) of the Durvalumab and Trabectedin Combination in the whole treated population and at the RP2D in the expansion cohort(s) | After 2 cycles of study drugs to study end date, up to 24 months. | ORR is determined by RECIST v1.1 and iRECIST response criteria. |
| Incidence of Treatment-Emergent Adverse Events (Safety) | Study start date to study end date, up to 24 months. | Number of participants with abnormal laboratory values and/or adverse events that are related to treatment. |
| Incidence of Treatment-Emergent Adverse Events (Tolerability) | Study start date to study end date, up to 24 months. | Number of participants with abnormal laboratory values and/or adverse events that are related to treatment. |
| One Year Overall Survival (OS) of the Durvalumab and Trabectedin Combination | Study start date to death from any cause, up to 24 months. | Determined continuously throughout the study. |
| Duration of Response (DOR) of the Durvalumab and Trabectedin Combination | After 2 cycles of study drugs, up to 24 months. | The time period for which a partial response (PR) or complete response (CR) is maintained. |
Outcome results
None listed