Alternative Dosing for CRLX101(NLG207) Alone, With Avastin and With mFOLFOX6 in Advanced Solid Tumors

Sponsor

NewLink Genetics Corporation (Industry)

Overall Status

Terminated

CT.gov ID

NCT02648711

Collaborator

(none)

Enrollment

Locations

Arms

31.2

Duration (Months)

13.7

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors	Drug: CRLX101 Drug: Bevacizumab Drug: mFOLFOX6	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Evaluation of an Alternative Schedule for CRLX101 Alone in Combination With Bevacizumab and in Combination With mFOLFOX6 in Subjects With Advanced Solid Tumor Malignancies

Study Start Date :

Oct 1, 2015

Actual Primary Completion Date :

Oct 17, 2017

Actual Study Completion Date :

May 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CRLX101 alone Subjects will receive weekly infusion of CRLX101 alone. Starting dose 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 will be explored.	Drug: CRLX101 infusion CRLX101 weekly Other Names: NLG207
Experimental: CRLX101 in combination with bevacizumab Subjects receive weekly infusion of CRLX101 in combination with bi-weekly bevacizumab (10 mg/kg. The starting dose is 12 mg/m^2 and the next dose level is 15 mg/m^2. No other dose levels will be explored.	Drug: CRLX101 infusion CRLX101 weekly Other Names: NLG207 Drug: Bevacizumab infusion weekly CRLX101 + bevacizumab biweekly Other Names: Avastin
Experimental: CRLX101 in combination with mFOLFOX6 Subjects receive weekly infusion of 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 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous infusion). The starting dose is 12 mg/m^2 and the next dose level is 15 mg/m^2.	Drug: CRLX101 infusion CRLX101 weekly Other Names: NLG207 Drug: mFOLFOX6 infusion weekly CRLX101 for 3 or every 4 weeks and in combination with bi-weekly mFOLFOX6 Other Names: oxaliplatin, leucovorin, 5FU

Arm

Intervention/Treatment

Experimental: CRLX101 alone

Subjects will receive weekly infusion of CRLX101 alone. Starting dose 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 will be explored.

Drug: CRLX101

infusion CRLX101 weekly

Other Names:

NLG207

Experimental: CRLX101 in combination with bevacizumab

Subjects receive weekly infusion of CRLX101 in combination with bi-weekly bevacizumab (10 mg/kg. The starting dose is 12 mg/m^2 and the next dose level is 15 mg/m^2. No other dose levels will be explored.

Drug: CRLX101

infusion CRLX101 weekly

Other Names:

NLG207

Drug: Bevacizumab

infusion weekly CRLX101 + bevacizumab biweekly

Other Names:

Avastin

Experimental: CRLX101 in combination with mFOLFOX6

Subjects receive weekly infusion of 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 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous infusion). The starting dose is 12 mg/m^2 and the next dose level is 15 mg/m^2.

Drug: CRLX101

infusion CRLX101 weekly

Other Names:

NLG207

Drug: mFOLFOX6

infusion weekly CRLX101 for 3 or every 4 weeks and in combination with bi-weekly mFOLFOX6

Other Names:

oxaliplatin, leucovorin, 5FU

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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) - 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)
Pharmacokinetic Profile (PK) - Plasma:t1/2 [15 months]
Plasma PK parameters will include half-life (t1/2)
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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Exclusion Criteria for Subjects Enrolled in Schedule 2 Only

Minor surgical procedure, excluding placement of a vascular access device, within 24 hours prior to W1D1.
Cardiovascular disease defined as congestive heart failure (NYHA Class II, III, or IV) per the NYHA Classification, angina pectoris requiring nitrate therapy, or myocardial infarction within the last 6 months prior to therapy
Uncontrolled hypertension (defined as the presence of systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg on two separate occasions. Blood pressure must be controlled to a systolic blood pressure <150 mmHg and/or to diastolic blood pressure <100 mmHg prior to study treatment), or any prior history of hypertensive crisis or hypertensive encephalopathy
Peripheral vascular disease >Grade 1
Known congenital long QT syndrome, history of torsades de pointes or ventricular tachycardia.
Known history of pulmonary hypertension or non-infectious interstitial pneumonitis.
History or evidence of thrombotic or hemorrhagic disorders: including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA), intracerebral hemorrhage or sub- arachnoid hemorrhage ≤ 6 months prior to W1D1
Chronic daily aspirin >325 mg/day or clopidogrel (>75 mg/day)
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization
Any of the following serious, non-healing conditions:wound, ulcer, or bone fracture
Proteinuria at screening as demonstrated by either: urine dipstick ≥2+ (subjects discovered to have a ≥2+ proteinuria on dipstick urinalysis at baseline should undergo 24-hour urine collection and must demonstrate <1g of protein in 24 hours to be eligible): 24-hour urine collection demonstrates >1g of protein in 24 hours
Immunocompromised subjects, including known seropositivity for human immunodeficiency virus (HIV), or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus [anti HCV] with confirmatory testing). [Note: testing is not mandatory to be eligible for the study. However, if a subject is at risk for having undiagnosed hepatitis C virus (HCV) (due to history of injection drug use or due to geographic location for example), testing at screening should be considered]
Chronic treatment with corticosteroids (prednisone >12.5 mg/day or dexamethasone >2 mg/day excluding inhaled steroids

Exclusion Criteria for Subjects Enrolled in Schedule 3 Only

Known hypersensitivity to 5FU, oxaliplatin or other platinum agent, or to their excipients
Known dihydropyridine dehydrogenase (DPD) enzyme deficiency (testing not required)
Baseline peripheral neuropathy grade ≥ 2
Progressive disease within ≤ 6 months of completing an oxaliplatin containing adjuvant therapy
Interstitial lung disease with ongoing signs and symptoms at the time of informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	START Midwest/Cancer & Hematology Centers of Western Michigan, PC	Grand Rapids	Michigan	United States	49503
2	MD Anderson Cancer Center	Houston	Texas	United States	77030
3	South Texas Accelerated Research Therapeutics (START), LLC	San Antonio	Texas	United States	78229