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Folic Acid-Tubulysin Conjugate EC1456 In Patients With Advanced Solid Tumors

This study is currently recruiting participants.
See Contacts and Locations
Verified April 2017 by Endocyte
Sponsor:
Information provided by (Responsible Party):
Endocyte
ClinicalTrials.gov Identifier:
NCT01999738
First received: November 26, 2013
Last updated: April 4, 2017
Last verified: April 2017
  Purpose

Phase 1A/B, multicenter, open-label, non-randomized, dose-escalation oncology study to evaluate the administration of EC1456 in advanced solid tumors. In part A, EC1456 will be dose escalated on 4 concurrently enrolling schedules. FR-positive expression on a 99mTc-etarfolatide scan is not required for inclusion in Part A.

Part B of the study will confirm the maximum tolerated dose (MTD) and the recommended Phase 2 (RP2) dose of EC1456, and evaluate the efficacy of EC1456 in NSCLC all subtype patient populations with FR-positive cancer in up to three schedules (i.e., twice weekly, once weekly, and four times weekly). FR-positive expression on a 99mTc-etarfolatide scan is required for inclusion in Part B.

Minimum length of patient participation is anticipated to be 10 weeks (two 3-week cycles followed by a 30 day follow-up period).


Condition Intervention Phase
Solid Tumors Non Small Cell Lung Carcinoma Drug: EC1456 and EC20 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase I A/B Study of the Folic Acid-Tubulysin Conjugate EC1456 In Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Endocyte:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2) - Part A [ Time Frame: 18-24 months ]

    Part A - To dose escalate EC1456 dose until maximum tolerated dose (MTD) and recommended Phase 2 (RP2) dose for multiple schedules is reached.

    -All patients who receive at least one dose of EC1456 will be evaluated for safety. All AEs and SAEs will be graded as per CTCAE V4.0. For each dose level, summaries of dose adjustments, adverse event rates, laboratory changes, cumulative toxicity, and dose limiting toxicity (DLT) will be analyzed. Summaries of CTCAE grades will be analyzed at each dose level and each cycle.


  • Efficacy Analysis - Part B [ Time Frame: 18-24 months ]
    Part B - Response to study therapy will be calculated per RECIST v1.1 criteria for all patients treated with at least one dose of EC1456


Estimated Enrollment: 220
Study Start Date: October 2013
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A - MTD (Treatment 1)

Treatment 1 is BIW on Days 1, 4, 8, and 11 of a 3-week schedule (BIW).

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide
Experimental: Part A - MTD (Treatment 2)

Treatment 2 is EC1456 QW on Days 1 and 8 of a 3-week schedule (QW).

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide
Experimental: Part A - MTD (Treatment 3)

Treatment 3 is EC1456 QW on Days 1, 8, and 15 of a 3-week schedule (CWD).

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide
Experimental: Part A - MTD (Treatment 4)

Treatment 4 is EC1456 QIW on Days 1, 2, 3, 4, 8, 9, 10, and 11 of a 3-week schedule (QIW).

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide
Experimental: Part B - Efficacy (Treatment 5)

Treatment 5 is EC1456 BIW. Once a dose is determined in Part A, Part B will begin with 3-6 subjects who will receive consecutive day dosing on Days 1, 2, 8, and 9 of a 3-week schedule. If this is not tolerated, the BIW cohort will continue with dosing on Days 1, 4, 8, and 11 of a 3-week schedule.

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide
Experimental: Part B - Efficacy (Treatment 6)

Treatment 6 is EC1456 QW on Days 1 and 8 of a 3-week schedule or CWD on Days 1, 8 and 15 of a 3-week schedule.

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide
Experimental: Part B - Efficacy (Treatment 7)

Treatment 7 is EC1456 QIW on Days 1, 2, 3, 4, 8, 9, 10, and 11 of a 3-week schedule for at least two cycles. If the patient is eligible to continue treatment (based upon treatment response and tolerability), he/she may opt to continue on the QIW schedule or change to the Treatment 6 regimen schedule (once its MTD and schedule have been determined).

Intervention: EC1456 and EC20

Drug: EC1456 and EC20

EC1456 is small molecule drug conjugate of folic acid and tubulysin B hydrazide (TubBH) that specifically binds to the membrane-bound FR and gains entry into the cell via endocytosis.

EC20 is Etarfolatide, a conjugate of folic acid and a tripeptide moiety that can efficiently chelate the radioisotope 99mTechnetium (99mTc). When etarfolatide is labeled with 99mTc, the product (99mTc-etarfolatide) is able to quantify FR expressing tissues with SPECT imaging.

Other Name: Folic acid and tubulysin B hydrazide and etarfolatide

Detailed Description:

In part A, EC1456 will be dose escalated on 4 concurrently enrolling schedules.

Treatment 1 is EC1456 BIW on Days 1, 4, 8, and 11 of a 3-week schedule (BIW); Treatment 2 is EC1456 QW on Days 1 and 8 of a 3-week schedule (QW); Treatment 3 is EC1456 QW on Days 1, 8, and 15 of a 3-week schedule (CWD) and Treatment 4 is EC1456 QIW on Days 1, 2, 3, 4, 8, 9, 10, and 11 of a 3-week schedule (QIW).

In part B, EC1456 will be dosed on 3 concurrently enrolling schedules:

Treatment 5 is EC1456 BIW. Once a dose is determined in Part A, Part B will begin with 3-6 subjects who will receive consecutive day dosing on Days 1, 2, 8, and 9 of a 3-week schedule. If this is not tolerated, the BIW cohort will continue with dosing on Days 1, 4, 8, and 11 of a 3-week schedule; Treatment 6 is EC1456 QW on Days 1 and 8 of a 3-week schedule or CWD on Days 1, 8 and 15 of a 3-week schedule; Treatment 7 is EC1456 QIW on Days 1, 2, 3, 4, 8, 9, 10, and 11 of a 3-week schedule for at least two cycles. If the patient is eligible to continue treatment (based upon treatment response and tolerability), he/she may opt to continue on the QIW schedule or change to the Treatment 6 regimen schedule (once its MTD and schedule have been determined).

  Eligibility

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

Inclusion Criteria:

Patients enrolled in Part A must receive the 99mTc- etarfolatide scan but they do not need to have FR-positive target lesions.

Parts A and B:

To qualify for enrollment, the following criteria must be met:

  1. Patient must have the ability to understand and sign an approved informed consent form (ICF).
  2. Patient must be ≥ 18 years of age.
  3. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  4. Patient must have a life expectancy of > 3 months.
  5. Patient must have at least one measurable lesion per RECIST v1.1 Criteria as assessed on baseline radiologic evaluation obtained no more than 28 days prior to beginning study therapy.
  6. Patients with central nervous system (CNS) metastases that are symptomatic must have received therapy (e.g., surgery, XRT, gamma knife, etc.) and be neurologically stable and off of steroids. The patient should be off steroids at least 14 days before registration. Patients with asymptomatic CNS metastatic disease without associated edema, shift, and a requirement for steroids or anti-seizure medications may be eligible after discussion with the sponsor medical monitor.
  7. Patients must have formalin fixed tissue (biopsy or FNA) available.
  8. Patient must have recovered (to baseline/stabilization) from prior chemo or radio therapy and associated acute toxicities must have resolved to a NCI CTCAE V4 Grade 1 or less, with the exception of alopecia.
  9. Patients treated with prior radiation therapy may be eligible if:

    1. Radiotherapy was completed at least 2 weeks before first dose of EC1456 and
    2. Patient has recovered from acute radiation toxicity.
  10. Patients must have adequate organ function:

    1. Bone marrow reserve: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9 g/dL.
    2. Cardiac:

    i. QTcFridericia (QTcF) < 450 msec on at least 2 of 3 screening ECG's. On site determination of QTcF may be used for screening purposes.

    ii. Left ventricular ejection fraction (LVEF) equal to or greater than the institutional lower limit of normal. LVEF must be evaluated within 28 days prior to C1D1.

    iii. Cardiac Troponin I or T within normal limit. (whichever troponin is done for screening will need to be done throughout the rest of the study).

    c. Hepatic: Total bilirubin ≤ 1.5 x the upper limit of normal (ULN); Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases.

    d. Renal: Serum creatinine ≤ 1.5 x ULN or for patients with serum creatinine > 1.5 ULN, creatinine clearance ≥ 50 mL/min.

    Patients of childbearing potential:

  11. All women of childbearing potential MUST have a negative urine or serum pregnancy test within 1 week prior to the 99mTc-etarfolatide imaging procedure and within 1 week prior to treatment with EC1456.
  12. Women of child bearing potential must practice an effective method of birth control (i.e., oral, transdermal or injectable contraceptives, intrauterine device [IUD], or double-barrier contraception, such as diaphragm and spermicidal jelly) for the duration of their participation in the trial through 90 days following the last dose of EC1456.
  13. Male patients who are sexually active must practice an effective method of birth control (e.g., condom and spermicidal jelly) for the duration of their participation in the trial through 90 days following the last dose of EC1456.

    Patient and Disease Specific Inclusion Criteria: Part A

    EC1456 dose escalation cohorts (Treatments 1, 2, 3, and 4):

  14. Patients must have pathologically confirmed metastatic or locally advanced solid cancer (preferably TNBC, NSCLC, ovarian, or endometrial cancers due to frequent high FR expression in these cancers) that has failed to respond to standard therapy, is not amenable to standard therapy, or for which standard therapy does not exist.
  15. TNBC and ovarian patients must agree to submit results of BRCA 1/2 status (i.e., deleterious mutation present, mutation of unknown significance, no mutation detected) if known. BRCA testing is not required for study inclusion.
  16. Patients must have received ≤ 4 prior lines of systemic anti-cancer therapy (including but not limited to cytotoxic agents, targeted inhibitors, and monoclonal antibodies). Hormonal therapies are not included toward this criterion.
  17. Patients must undergo a 99mTc-etarfolatide SPECT imaging procedure in compliance with the Investigator's Imaging Operations Manual (IIOM). FR expression on 99mTc -etarfolatide SPECT is not required for inclusion in Treatments 1, 2, 3, and 4.

    (Patients who underwent a 99mTc-etarfolatide SPECT/CT imaging procedure as a subject on Endocyte study EC20.12 will not be required to have a repeat scan for participation in study EC1456-01 if the scan was obtained within 4 weeks of cycle 1 day 1 of EC1456 administration and has been deemed acceptable by Endocyte Imaging.)

    Part B Only:

    Patient and Disease Specific Inclusion Criteria: Part B

    Patients with FR-positive NSCLC (all subtypes): (Treatments 5, 6, and 7)

  18. Patients with NSCLC (all subtypes) must have received one prior platinum based therapy for advanced or metastatic disease. No additional cytotoxic therapy for advanced or metastatic disease is allowed. Any number of prior targeted therapies (e.g., inhibitors of ALK, EGFR, and PD-1 or PD-L1) are allowed. Patients with known relevant genomic tumor aberrations (i.e., EGFR, ALK, ROS-1, etc) must have received and progressed on approved therapy for these aberrations. This information must be documented prior to study entry.
  19. Patients must undergo a 99mTc-etarfolatide SPECT imaging procedure in compliance with the Investigator's Imaging Operations Manual (IIOM) and be FR-positive.

Exclusion Criteria:

Parts A and B:

The presence of any of the following will exclude patients from the study:

  1. Systemic anti-cancer treatment, except hormonal treatment, within 28 days prior to EC1456 administration unless there are no remaining or ongoing uncontrolled toxicities. Please contact the medical monitor to discuss requests for less than 28 day washout period.
  2. Known hypersensitivity to the components of the study therapy or its analogs.
  3. Carcinomatous meningitis and/or symptomatic central nervous system (CNS) metastases.
  4. Malignancies that are expected to alter life expectancy or may interfere with disease assessment. Patients with adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or low-grade (Gleason score ≤ 6) localized prostate cancer, ductal carcinoma in situ (DCIS), and patients with prior history of malignancy who have been disease free for more than 3 years are eligible.
  5. Serious cardiac illness or medical conditions such as unstable angina, pulmonary embolism, or uncontrolled hypertension.
  6. Patients considered at risk for life-threatening QTc prolongation (i.e., personal or family history of Long QT syndrome, presence of implantable pacemaker or implantable cardioverter defibrillator, etc.).
  7. Use of the following medications within 6 months prior to EC1456 administration: amiodarone, disopyramide, dofetilide, dronedarone, flecanamide, ibutilide, quinidine, or sotalol.
  8. Need for concurrent anti-folate therapy such as methotrexate for rheumatoid arthritis.
  9. Other concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy.
  10. Pregnant or lactating women.
  11. Active uncontrolled infections.
  12. Known active Hepatitis B or C infection.
  13. Unable or unwilling to have a pretreatment scan performed with 99mTc-etarfolatide for any reason (such as claustrophobia, an inability to lie supine on an imaging table because of pain or cardiopulmonary disease, etc.).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01999738

Contacts
Contact: Doria Kaluza 317-608-0586 dkaluza@endocyte.com
Contact: Wendy Perez 317-608-0590 wperez@endocyte.com

Locations
United States, Arizona
Mayo Clinic Recruiting
Phoenix, Arizona, United States, 85054
Contact: Helen Ross, MD         
Contact: Katie Gano    480-342-6082    gano.katherine@mayo.edu   
Principal Investigator: Helen Ross, MD         
Honor Health Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Jasgit Sachdev, MD    480-323-1350    jasgit.sachdev@honorhealth.com   
Contact: S. Danielle LeGrand, RN, BSN    480-323-1241    sarah.legrand@honorhealth.com   
Principal Investigator: Jasgit Sachdev, MD         
University of Arizona Cancer Center Recruiting
Tucson, Arizona, United States, 85719
Contact: Linda Garland, MD    520-626-2225    lgarland@uacc.arizona.edu   
Contact: Lisa Slayton    520-694-9057    lslayton@uacc.arizona.edu   
Principal Investigator: Linda Garland, MD         
United States, California
City of Hope Not yet recruiting
Duarte, California, United States, 91010
Contact: Ravi Salgia, MD    626-256-4673    rsalgia@coh.org   
Principal Investigator: Ravi Salgia, MD         
United States, District of Columbia
Georgetown University Lombardi Comprehensive Cancer Center Withdrawn
Washington, District of Columbia, United States, 20007
United States, Illinois
Northwestern University Robert H. Lurie Comprehensive Cancer Center Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Young Chae, MD    312-926-4248    young.chae@northwestern.edu   
Principal Investigator: Young Chae, MD         
United States, Indiana
IU Health Goshen Center for Cancer Care Recruiting
Goshen, Indiana, United States, 46526
Contact: Daniel Bruetman, MD    574-536-5462    dbruetma@goshenhealth.com   
Contact: Vanessa DePue, RN    574-364-2986    vdepue@goshenhealth.com   
Principal Investigator: Daniel Bruetman, MD         
Indiana University Cancer Center Terminated
Indianapolis, Indiana, United States, 46202
Horizon BioAdvance Recruiting
Lafayette, Indiana, United States, 47905
Contact: Wael Harb, MD    765-446-5111    wharb@horizonbioadvance.com   
Contact: Elizabeth Morris    765-446-5111    emorris@horizonbioadvance.com   
Principal Investigator: Wael Harb, MD         
United States, Maryland
University of Maryland-Greenebaum Cancer Center Recruiting
Baltimore, Maryland, United States, 21201-1595
Contact: Edward Sausville, MD    410-328-7395    esausville@umm.edu   
Contact: Navid Saeidi    410-328-6465    navid.saeidi@umm.edu   
Principal Investigator: Edward Sausville, MD         
United States, Michigan
Henry Ford Hospital - Josephine Ford Cancer Center Recruiting
Detroit, Michigan, United States, 48202
Contact: Ding Wang, MD    313-916-1784    dwang1@hfhs.org   
Contact: Kris Strzalkowski    313-916-7450    kstrzal1@hfhs.org   
Principal Investigator: Ding Wang, MD         
United States, New York
Roswell Park Cancer Institute Not yet recruiting
Buffalo, New York, United States, 14203
Contact: Grace Dy, MD    716-845-3099    grace.dy@roswellpark.org   
Contact: Askia Dozier    716-845-4387    askia.dozier@roswellpark.org   
Principal Investigator: Grace Dy, MD         
Weill Cornell Medical College Recruiting
New York, New York, United States, 10021
Contact: Ashish Saxena, MD    646-962-2066    ahs9018@med.cornell.edu   
Contact: Alexandra Mavracick    646-962-8169    alm2074@med.cornell.edu   
Principal Investigator: Ashish Saxena, MD         
United States, Ohio
University Hospitals Case Medical Center - Seidman Cancer Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Afshin Dowlati, MD    216-286-6741    afshin.dowlati@uhhospitals.org   
Contact: Kyle Logue, PhD    216-286-1090    kyle.logue@uhhospitals.org   
Principal Investigator: Afshin Dowlati, MD         
United States, Tennessee
Vanderbilt University Medical Center Withdrawn
Nashville, Tennessee, United States, 37232
United States, Texas
Westchase Clinical Associates Terminated
Houston, Texas, United States, 77042
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77230
Contact: Siqing Fu, MD    713-792-4318    siqingfu@mdanderson.org   
Contact: Yan Zhang    713-794-3601    yzhang32@mdanderson.org   
Principal Investigator: Siqing Fu, MD         
United States, Vermont
University of Vermont Cancer Center Recruiting
Burlington, Vermont, United States, 05401
Contact: Steven Ades, MD    802-847-8400    steven.ades@uvmhealth.org   
Contact: Sam Cory, CRCC    802-656-9446    samuel.cory@med.uvm.edu   
Principal Investigator: Steven Ades, MD         
Sponsors and Collaborators
Endocyte
Investigators
Study Director: Alison Armour, MD Endocyte
  More Information

Responsible Party: Endocyte
ClinicalTrials.gov Identifier: NCT01999738     History of Changes
Other Study ID Numbers: EC1456-01
Study First Received: November 26, 2013
Last Updated: April 4, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Folic Acid
Vitamin B Complex
Hematinics
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 23, 2017