Advance Solid Malignancies, Metastatic Solid Malignancies
Conditions
Keywords
selinexor, nivolumab, ipilimumab
Brief summary
This is a single-centre, phase 1a (dose escalation) and 1b (dose expansion) study to evaluate the safety and tolerability of oral Selinexor in combination with nivolumab and ipilimumab in patients with advanced solid malignancies.
Detailed description
Primary Objectives * To evaluate the safety and tolerability of selinexor in combination with nivolumab and ipilimumab * To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) of selinexor in combination with nivolumab and ipilimumab in patients with advanced or metastatic solid tumor malignancies. Secondary Objectives * To determine Selinexor pharmacokinetics (PK) in Asian patients * To describe anti-tumor responses with the combination in patients with advanced or metastatic solid tumor malignancies. Exploratory Objectives * To assess the immunomodulatory effects of selinexor in solid tumour malignancies and circulating immune cells * To identify biomarkers of response to the combination of selinexor and nivolumab + ipilimumab. We will explore changes in PDL1 expression, T cell infiltration (including CD4 and CD8 positive cells), gene expression profiles on serial tumor biopsies pre-selinexor, post-selinexor alone, and after the combination of selinexor and ipilimumab + nivolumab where feasible.
Interventions
DRUGSelinexor in combination with nivolumab and ipilimumab
Patients will commence at dose level 1. One cycle is 42 days (6 weeks) for all three agents. At dose level 1, selinexor will be dosedorally weekly, and nivolumab at 2 weekly + ipilimumab 1mg/kg 6 weekly. Patients can have dosing interruptions or reductions of any drug independently of one another, depending on the drug causing the toxicity
Sponsors
National University Hospital, Singapore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
For all patients, the phase I drug combination will be preceded by a 14-day run in period where selinexor alone will be administered and biopsies will be obtained both pre-and post selinexor dosing. Patients will be treated with all three drugs until disease progression (as defined by RECIST criteria) or intolerable drug toxicity.
Eligibility
Sex/Gender
ALL
Age
21 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 21 2. Willing and able to provide written informed consent in accordance with local institutional guidelines. 3. Dose Escalation Phase: Patients with histologically or cytologically confirmed advanced or metastatic solid tumors who have radiological evidence of progressive disease on study entry that is deemed unlikely to benefit from further standard therapy. 4. Dose Expansion phase: Patients with previously treated, metastatic or advanced recurrence malignancy confirmed histologically or cytologically. Patients must have evidence of progressive disease on study entry that is deemed unlikely to benefit from further standard therapy. 5. There is no upper limit on the number of prior treatments. Hormone ablation therapy is considered an anticancer regimen. Radiation and surgery are not considered anticancer regimens. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1. 7. Adequate hepatic function within 14 days prior to C1D1: 1. Total bilirubin \< 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of \< 3 × ULN), and 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to \<3 × ULN. 8. Adequate renal function within 14 days prior to C1D1 as determined by serum creatinine of ≤1.5 mg/dL OR estimated creatinine clearance of ≥ 30 mL/min, calculated using the Cockcroft and Gault formula (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female. 9. Adequate hematopoietic function within 14 days prior to C1D1. Transfusions and growth factors are allowed prior to and throughout the study. 1. Total white blood cell (WBC) count ≥1500/mm3, absolute neutrophil count ≥1000/mm3 2. Hemoglobin ≥9 g/dL 3. Platelet count ≥125,000/mm3 in dose escalation phase, and platelet count ≥100,000/mm3 in dose expansion phase. 10. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 5 months following the last dose of study treatment. a. Female patients of childbearing potential and fertile male patients must agree to use highly effective contraception listed below (ie, results in a low failure rate when used consistently and correctly) during the dosing period and for a period of at least 5 months after the end of treatment. b. Highly effective methods include: i. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: 1\. oral 2. intravaginal 3. transdermal ii. progestogen-only hormonal contraception associated with inhibition of ovulation: 1. oral 2. injectable 3. implantable iii. intrauterine device iv. intrauterine hormone-releasing system v. bilateral tubal occlusion vi. vasectomized partner vii. sexual abstinence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective disease response assessment | 3 years | to be made according to standard, international RECIST 1.1 criteria for solid tumors. |
| progression free survival (PFS) | 3 years | the time interval from the starting date of combination treatment to the date of disease progression on treatment |
| duration of response (DOR) | 3 years | is defined as the time from documentation of tumor response to disease progression |
| Duration of stable disease | 3 years | is defined as the time from first RECIST assessment scan documenting stable disease by RECIST criteria, to disease progression |
Countries
Singapore
Outcome results
None listed