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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02648711
Recruitment Status : Terminated (Company decision)
First Posted : January 7, 2016
Last Update Posted : May 28, 2020
Sponsor:
Information provided by (Responsible Party):
Lumos Pharma ( NewLink Genetics Corporation )

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.

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Study Type : Interventional  (Clinical Trial)
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 : October 2015
Actual Primary Completion Date : October 17, 2017
Actual Study Completion Date : May 7, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

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 Name: 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 Name: NLG207

Drug: Bevacizumab
infusion weekly CRLX101 + bevacizumab biweekly
Other Name: 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 Name: NLG207

Drug: mFOLFOX6
infusion weekly CRLX101 for 3 or every 4 weeks and in combination with bi-weekly mFOLFOX6
Other Name: oxaliplatin, leucovorin, 5FU




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D) [ Time Frame: 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 :
  1. 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. [ Time Frame: 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.

  2. Pharmacokinetic Profile (PK) - Urine [ Time Frame: 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.

  3. Pharmacokinetic Profile (PK) - Plasma:CL [ Time Frame: 15 months ]
    Plasma PK parameters will include clearance (CL) for both total and unconjugated drug.

  4. Pharmacokinetic Profile (PK) - Plasma:Vd [ Time Frame: 15 months ]
    The plasma PK parameters will include volume of distribution (Vd)

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

  6. Pharmacokinetic Profile (PK) - Plasma:Cmax [ Time Frame: 15 months ]
    Plasma PK parameters will include maximum concentration (Cmax)

  7. Pharmacokinetic Profile (PK) - Plasma:AUC [ Time Frame: 15 months ]
    Plasma PK parameters will include area under the concentration versus time curve (AUC)

  8. Anti-tumor Activity [ Time Frame: 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02648711


Locations
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United States, Michigan
START Midwest/Cancer & Hematology Centers of Western Michigan, PC
Grand Rapids, Michigan, United States, 49503
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
South Texas Accelerated Research Therapeutics (START), LLC
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
NewLink Genetics Corporation
Investigators
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Study Chair: NewLink Ge NewLink Genetics Inc
Publications:
American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.
Keefe, SM, Heitjan D, Hennessy M., et al. Interim results of a phase 1b/2a study evaluating the nano pharmaceutical CRLX101 with bevacizumab (bev) in the treatment of subjects (pts) with refractory metastatic renal cell carcinoma (mRCC). J Clin Oncol 32, 2014 (suppl 4; abstr 412).
Yen et al, Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in subjects with advanced solid tumor malignancies, 23rd EORTC-NCI-AACR, Nov 12-16, 2011: abstract A97
Bissery MC, Vrignaud P, Lavelle F. In vivo evaluation of the irinotecan-oxaliplatin combination. Proc Am Assoc Cancer Res 1998; 39: 526.
Ychou M, Desseigne F, Guimbaud R et al. Randomized phase II trial comparing folfirinox (5FU/leucovorin [LV], irinotecan [I] and oxaliplatin [O] vs gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA). First results of the ACCORD 11 trial [abstract]. J Clin Oncol 2007;25(June 20 Suppl):4516.
Lowery MA, Yu KH, Adel NG et al. Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma (PC) at Memorial Sloan-Kettering Cancer Center (MSKCC) [abstract]. ASCO Meeting Abstracts 2012;30:4057.

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Responsible Party: NewLink Genetics Corporation
ClinicalTrials.gov Identifier: NCT02648711    
Other Study ID Numbers: CRLX101-102
First Posted: January 7, 2016    Key Record Dates
Last Update Posted: May 28, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Lumos Pharma ( NewLink Genetics Corporation ):
solid tumors
Additional relevant MeSH terms:
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Neoplasms
Leucovorin
Bevacizumab
Oxaliplatin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients