Solid Tumors
Conditions
Keywords
solid tumors
Brief summary
The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of weekly dosing of CRLX101 (both as monotherapy; (Schedule 1) and in combination with bevacizumab every 2 weeks (Schedule 2) and weekly with a 3 week on / 1 week off schedule in combination with mFOLFOX6 (Schedule 3) to affirm the dose for future clinical studies.
Detailed description
This is an open-label, dose escalation study. Subjects enrolled in Schedule 1 will receive weekly CRLX101 alone. The starting dose for Schedule 1 is 12 mg/m\^2 and the next dose level is 15 mg/m\^2 (or 10 mg/m\^2 if 12 mg/m\^2 is not well tolerated). No other dose levels in Schedule 1 will be explored. Subjects enrolled in Schedule 2 will receive weekly CRLX101 in combination with bi-weekly bevacizumab (10 mg/kg) The starting dose for Schedule 2 is 12 mg/m\^ and the next dose is 15 mg/m\^2. No other dose levels in Schedule 2 will be explored Subjects enrolled in Schedule 3 will receive weekly CRLX101 for 3 of every 4 weeks in combination with bi-weekly mFOLFOX6 (oxaliplatin 85 mg/m\^2, leucovorin 400 mg/m\^2 and 5FU (fluorouracil) 400 mg/m\^2 bolus followed by 2400 mg/m\^2 continuous infusion). The starting dose for Schedule 3 is 12 mg/m\^2 and the next dose is 15 mg/m\^2. In the absence of dose-limiting toxicities (DLTs) additional subjects may be enrolled (expansion cohort) at the same, intermediate or lower dose levels following consultation between the Investigator and Sponsor. Enrollment of 6-8 subjects will occur in each cohort for all 3 Schedules. The MTD is defined as the highest dose level at which fewer than 2 out of 6 subjects experience a DLT. RP2D will be selected based on overall tolerability data from all subjects treated at different dose cohorts in this study. No intra-patient dose escalation is allowed. Approximately 61 evaluable subjects are anticipated to be enrolled: 15 subjects in Schedule 1, 15 subjects in Schedule 2 and approximately 31 subjects are anticipated in Schedule 3 (approximately 16 in the dose escalation cohort and up to 15 in the expansion cohort). The exact number of subjects is dependent on the actual number of subjects enrolled per cohort and the number of cohorts investigated.
Interventions
DRUGCRLX101
infusion CRLX101 weekly
DRUGBevacizumab
infusion weekly CRLX101 + bevacizumab biweekly
DRUGmFOLFOX6
infusion weekly CRLX101 for 3 or every 4 weeks and in combination with bi-weekly mFOLFOX6
Sponsors
NewLink Genetics Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(All Subjects) * Male or female adult subjects ≥18 years of age * Diagnosis of histologically or cytologically confirmed for: * For Schedule 1 and 2: advanced solid tumor malignancy that is refractory to standard therapy and/or for whom no further standard therapy is available * For Schedule 3: advanced/metastatic tumors for which mFOLFOX6 is appropriate, or advanced/metastatic tumors that may be sensitive to each component of mFOLFOX6 or sensitive to topoisomerase 1 inhibitors including pancreatic, colorectal, esophageal, gastric, bladder or ovarian cancer, triple-negative breast cancer, small cell lung cancer (SCLC), cholangiocarcinoma, among others * For Schedules 1 and 2: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, For Schedule 3: ECOG Performance Status of 0 or 1 * Life expectancy \>12 weeks in the opinion of the Investigator * Subjects with acceptable pre-study\* hematology and biochemistry labs ≤3 days prior to Week 1 Day 1 (W1D1) defined as: * absolute neutrophil count (ANC) ≥1.500 cells / µL (1.5 x 10°/L, without growth factor support * platelet count ≥100,000 cells/µL (100 x 10° cells/L), without growth factor support * hemoglobin ≥9 g/dL (90/g/L) * serum total bilirubin ≤1.5 upper limit of normal (ULN), unless Gilbert's disease * alanine transaminase (ALT) or aspartate transaminase (AST) ≤2.5 x ULN, (5 x ULN for subjects with liver metastases) * calculated or measured creatinine clearance ≥40 mL/min * NOTE: If screening hematology and biochemistry labs are performed ≤3 days prior to W1D1, additional pre-study labs do not need to be repeated to confirm eligibility. However, if screening hematology and biochemistry labs are performed greater than 3 days prior to W1D1, additional pre-study labs will need to be performed to confirm continued eligibility to ensure labs remain acceptable per protocol * Females of childbearing potential must agree to use two effective methods of contraception (or abstain completely from heterosexual intercourse) from the time of informed consent and for 30 days following last dose of study drug * NOTE: Females of childbearing potential are defined as women physically capable of becoming pregnant unless the female subject cannot have children due to surgery or other medical reasons (effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Fertile males of childbearing potential are defined as men who are sexually capable to impregnate the female partner even if surgically sterilized (i.e., vasectomy). * highly effective methods of contraception include intra-uterine device (IUD) and hormonal contraception (oral, injectable, patches or implant) * effective methods of contraception include barrier methods (latex condom, diaphragm with spermicide, cervical cap, sponge) * when possible, subjects should be strongly encouraged to include at least one highly effective method of contraception * Male subjects must agree to use appropriate method of barrier contraception (latex condom with a spermicidal agent) or abstain completely from heterosexual intercourse fro the time of informed consent and for 120 days following last dose of study drug unless female partner absolutely cannot have children because of surgery or for other medical reasons * Negative urine pregnancy test * Ability to understand and willingness to sign a written informed consent form * Able to comply with study visit schedule and assessments
Exclusion criteria
(All Subjects) * Subject has received: * chemotherapy or small molecular targeted therapy \<2 weeks prior to W1D1 * approved antibody therapy \<5 half-lives from W1D1 (or 4 weeks since last therapy, whichever is the shortest) * local palliative radiation \<14 days from W1D1 * invasive surgery requiring general anesthesia \<30 days from W1D1 * chemotherapy with nitrosoureas or mitomycin C \<45 days from W1D1 * Uncontrolled grade 2 or greater toxicity except alopecia related to any prior treatment (i.e., chemotherapy, targeted therapy, radiation or surgery) within 7 days prior to W1D1 unless approved by the Medical Monitor * Prolongation of QT/QTc interval (QTc interval \>470) using the Fredericia method of QTc analysis * Women who are pregnant or nursing * Any known human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS) or any concurrent infection requiring IV antibiotics * Any known clinically significant or concurrent acute liver disease, including viral hepatitis * Primary brain malignant tumors * Subjects with uncontrolled symptomatic central nervous system (CNS) involvement * Subjects requiring steroids at stable dose (\>4 mg/day dexamethasone or equivalent) for at least 2 weeks * Uncontrolled hypertension \>150/100 mmHg * Concurrent participation in any other investigational therapeutic study, unless non-interventional study and approved by Sponsor * History of stroke, deep venous thrombosis (DVT), transient ischemic attack (TIA), unstable angina, or myocardial infarction within 3 months prior to W1D1 * Uncontrolled concurrent disease or illness including but not limited to: * symptomatic congestive heart failure (NYHA Class III or IV) per the NYHA Classification, unstable angina pectoris, clinically significant cardiac arrhythmia * unstable or untreated cardiac conditions or ejection fraction of \<50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) * diabetes mellitus (i.e., fasting blood glucose \>220 despite acceptable chronic diabetes therapy) * psychiatric illness that would limit compliance with study requirements, as determined by the Investigator * Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for the study. * Known hypersensitivity to any component of CRLX101 or excipient or documented medical condition that would prohibit adequate pre-medication with antihistamine. * Presence of ≥Grade 1 cystitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D) | 15 months | To determine the maximum tolerated dose (MTD) / recommended Phase 2 dose (RP2D) of CRLX101 when administered by intravenous (IV) infusion every week (QW) alone (Schedule 1), (QW) in combination with bevacizumab (Q2W) (Schedule 2) and weekly with a 3-week on / 1-week off schedule in combination with mFOLFOX6 (Q2W) (Schedule 3) in subjects with advanced solid tumor malignancies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Profile (PK) - Urine | 15 months | Urine samples will be collected to evaluate the urinary excretion of total and unconjugated drug before, during, and after infusion. PK parameters in urine will include the maximum concentration (Cmax), amount of drug in the urine, % of drug eliminated in the urine. PK parameters will be calculated using non-compartmental analysis. Actual sampling times will be used to calculate PK parameters in this study. |
| Pharmacokinetic Profile (PK) - Plasma:CL | 15 months | Plasma PK parameters will include clearance (CL) for both total and unconjugated drug. |
| Pharmacokinetic Profile (PK) - Plasma:Vd | 15 months | The plasma PK parameters will include volume of distribution (Vd) |
| Safety and Tolerability (Weekly Dosing) determined by reported adverse events, serious adverse events, physical exam findings, vital sign measurements,12-lead ECG readings, clinical lab evaluations, and treatment discontinuation due to toxicity. | 15 months | Will be determined by reported AEs, SAEs, physical exam findings, vital sign measurements,12-lead ECG readings, clinical lab evaluations, and treatment discontinuation due to toxicity. |
| Pharmacokinetic Profile (PK) - Plasma:Cmax | 15 months | Plasma PK parameters will include maximum concentration (Cmax) |
| Pharmacokinetic Profile (PK) - Plasma:AUC | 15 months | Plasma PK parameters will include area under the concentration versus time curve (AUC) |
| Anti-tumor Activity | 15 months | To further explore preliminary signs of anti-tumor activity of CRLX101 when administered alone (Schedule 1) and in combination with bevacizumab (Schedule 2), and in combination with mFOLFOX6 (Schedule 3) |
| Pharmacokinetic Profile (PK) - Plasma:t1/2 | 15 months | Plasma PK parameters will include half-life (t1/2) |
Countries
United States
Outcome results
None listed