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Safety, Tolerability, PK/PD of FE 203799 in Adults With Lymphomas

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: NCT03417765
Recruitment Status : Withdrawn (Business decision)
First Posted : January 31, 2018
Last Update Posted : October 26, 2018
Sponsor:
Information provided by (Responsible Party):
GLyPharma Therapeutic

Brief Summary:

RATIONALE:

The integrity of the intestinal mucosa is a key factor for the preservation of a normal gut function. Damage of the epithelium (i.e. by chemotherapy) results in significant cellular and molecular alterations that ultimately lead to intestinal dysfunction/failure. This intestinal dysfunction manifests as several pathological processes, such as inability to absorb nutrients, intestinal inflammation, immune system dysregulation, and disequilibrium of normal intestinal microbiota leading to increased risk of infection due to bacterial translocation and septicaemia. Gastrointestinal (GI) mucositis is a well-known, frequent and debilitating side effect of most anticancer regimens with a very high incidence in hemato-oncology. The most common symptoms are nausea, vomiting, weight loss, abdominal cramps and pain, diarrhea, and electrolyte imbalance. Patients may also experience ulceration/bleeding and injury of the lining of the entire gastrointestinal tract from the esophagus to the colon. Currently no therapy is available for the prevention or treatment of GI intestinal injury. Treatment of related symptoms is limited to supportive measures to decrease diarrhea and to preventive antibiotic therapy. The GLP-2 analogue, FE 203799, has a favorable pharmacology profile for clinical development in the intended therapeutic indication of myeloablative chemotherapy-induced GI damage. The data collected from animal studies has shown that FE 203799 stimulates the proliferation of the intestinal epithelium and protects the GI mucosa from chemotherapy-induced injury. Hence, the primary pharmacologic activity of FE 203799 would promote a healthy GI microenvironment, thus preventing intestinal dysfunction and related complications.

PURPOSE: Prevention by FE 203799 of chemotherapy-induced intestinal damage and related complications in patients with lymphoma receiving Melphalan based (BEAM) myeloablative conditioning regimen followed by hematopoietic stem cell transplantation.


Condition or disease Intervention/treatment Phase
Lymphoma, Non-Hodgkin's, Adult Lymphoma, Hodgkin's, Adult Drug: FE 203799 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Placebo-control, ascending dose
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Supportive Care
Official Title: Double-blind, Placebo Controlled, Ascending Dose, Randomized Phase 1B/2A Study, Investigating Safety, Tolerability, PK/PD of FE 203799 in Lymphoma Patients, Undergoing Myeloablative Chemotherapy Before Autologous Transplantation
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : March 31, 2019
Estimated Study Completion Date : March 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Cohort A: 5 mg (FE 203799/Placebo)
Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation
Drug: FE 203799
GLP-2 analogue, once weekly, subcutaneous administration

Experimental: Cohort B: 10 mg (FE 203799/Placebo)
Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation
Drug: FE 203799
GLP-2 analogue, once weekly, subcutaneous administration

Experimental: Cohort C: 25 mg (FE 203799/Placebo)
Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation
Drug: FE 203799
GLP-2 analogue, once weekly, subcutaneous administration




Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse events [ Time Frame: Day -8 to Day 100 ]
    Adverse events as assessed by CTCAE v4.03


Secondary Outcome Measures :
  1. Maximum observed plasma concentration (Cmax) of FE 203799 [ Time Frame: Day -8 to Day 13 ]
    Cmax in ng/ml

  2. Cumulative area under the plasma concentration (AUC) time curve from 0-168 hours of FE 203799 [ Time Frame: Day -8 to Day 13 ]
    AUC0-168 in ng*hr/ml

  3. Cumulative area under the plasma concentration (AUC) from time zero to infinity of FE 203799 [ Time Frame: Day -8 to Day 13 ]
    AUC0-inf in ng*hr/ml

  4. Terminal elimination half-life (T1/2) of FE 203799 [ Time Frame: Day -8 to Day 13 ]
    T1/2 in hours

  5. Apparent total body clearance (CL) of the drug from plasma of FE 203799 [ Time Frame: Day -8 to Day 13 ]
    CL in ml/hr

  6. Apparent volume of distribution (Vz) of FE 203799 during terminal phase [ Time Frame: Day -8 to Day 13 ]
    Vz in ml

  7. Biomarker assessment for gut healing [ Time Frame: Day -8 to Day -1, Day 1 to Day 14 and Day 30 ]
    Plasma concentration of citrulline (ng/ml)

  8. Biomarker assessment for gut inflammation [ Time Frame: Day -8 to Day -1, Day 1 to Day 14 and Day 30 ]
    Plasma concentration of C-Reactive Protein (ng/ml)

  9. Assessment of infection - Incidence and duration of fever [ Time Frame: Day -8 to Day 20 and Day 30 ]
    Body temperature ≥38.2oC

  10. Assessment of infection - Incidence and duration of neutropenic fever [ Time Frame: Day -8 to Day 20 and Day 30 ]
    Development of fever when absolute neutrophil count (ANC) ≤ 0.5 x 109 and body temperature ≥ 38.2 ◦C for two consecutive values over a 30 minute period of time; or ANC < 0.5 x 109 and body temperature ≥ 38.5◦C at any single timepoint

  11. Incidence of microbiologically detected infection [ Time Frame: Day 5 to Day 15 ]
    Blood cultures once daily

  12. Assessment of gastrointestinal mucositis and related clinical symptoms [ Time Frame: Day -8 to Day 20 and Day 30 ]
    Grading as by the CTCAE v4.03

  13. Assessment of gastrointestinal mucositis by video-capsule endoscopy [ Time Frame: Day -8, Day 6 and Day 20 ]
    Gastrointestinal damage assessed by the Lewis Score; this is evaluation of villous edema, ulcers and stenosis graded collectively; Normal < 135, Mild 135-790, Moderate - severe ≥790

  14. Assessment of nutrients absorption [ Time Frame: Days -8, -1, 6, 13 and 30 ]
    Body weight (kg)

  15. Assessment of nutrients absorption [ Time Frame: Days -8, 0, 3, 6, 9, 12, 15, 18 ]
    Assessment of duration of parenteral nutrition (L)

  16. Assessment of nutrients absorption [ Time Frame: Days -8, 0, 3, 6, 9, 12, 15, 18 ]
    Assessment of caloric intake (calories)

  17. Microbiome composition [ Time Frame: Once a week over 4 weeks ]
    Determination of microbial populations by genomic analysis (relative abundance of taxonomic levels)

  18. Time to neutrophil and platelet engraftment [ Time Frame: Day-8 and then on Days -2, 5, 12 and 30 ]
    Hematological analysis

  19. Assessment of quality of life [ Time Frame: Days -8, -1, 6, 13 and 30 ]
    Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult male and non-pregnant or lactating female patients diagnosed with Hodgkin's lymphoma (HL) or non- Hodgkin's lymphoma (NHL; T- or B-cell variants) based on histological or cytological evidence.
  2. Patients are eligible to receive myeloablative chemotherapy as per center eligibility criteria, followed by AHSCT.
  3. Patients between 18 years and 65 years of age with a Hematopoietic Cell Transplant- Co-morbidity Index (HCT-CI) ≤5. Patients between 65 years and 70 years will be eligible if their HCT-CI score is ≤3.
  4. Patients, or their legal representatives, must have the ability to read, understand and provide written informed consent prior to the initiation of any study related procedures.
  5. Patients must have chemo-sensitive disease and be in partial or complete remission following the most recent anti-neoplastic therapy regimen, according to the Lugano revision of the International Working Group (IWG) response criteria [1].
  6. Patients must have available a cryopreserved autologous hematopoietic stem cell graft containing ≥ 2.0 x 106 cryopreserved CD34+ cells/kg.
  7. Patients must have a Karnofsky score ≥ 70%.
  8. Patients must have adequate hepatic function as evidenced by bilirubin ≤ upper limit of normal (ULN), unless felt to be related to Gilbert's syndrome or hemolysis; patients must also have AST and ALT ≤ 1.5 x ULN and alkaline phosphatase ≤ 2.5 x ULN.
  9. Patients must have an estimated or measured creatinine clearance ≥ 30 ml/min/1.73 m2 by the Cockcroft-Gault equation.
  10. Patients must have left ventricular ejection fraction ≥ 50%.
  11. Patients must have forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and diffusing capacity corrected for hemoglobin (DLCOc) ≥ 50% of predicted.
  12. Patients must have recovered from the effects of any prior chemotherapy, radiotherapy or surgery; for patients who have been on monoclonal antibody therapy, at least one half-life or 4 weeks (whichever is longer) should have elapsed prior to the first scheduled day of dosing with FE 203799.
  13. A female recipient of childbearing potential must meet the following criteria:

    1. Participant has a negative pregnancy test at Screening.
    2. Participant agrees to use one of the accepted contraceptive regimens from at least 14 days prior to the first administration of the Study Drug, during the study and for at least 90 days after the last dose of the Study Drug. An acceptable method of contraception includes one of the following:

      • Abstinence from heterosexual intercourse
      • Systemic contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
      • Intrauterine device (with or without hormones)
      • Diaphragm with spermicidal gel
      • Condom with spermicide gel
  14. A male patient, with sexual partners who are pregnant, possibly pregnant, or who could become pregnant, agrees to use one of the accepted contraceptive regimens throughout the entire duration of the study and until at least 3 months after the last drug administration. An acceptable method of contraception includes one of the following:

    • Abstinence from heterosexual intercourse
    • Condom with spermicide

Exclusion Criteria:

  1. Patient is unable or unwilling to give informed consent.
  2. Patients who are unable to comply with the treatment protocol including appropriate supportive care, follow-up and tests.
  3. Patients with known hypersensitivity to FE 203799, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions to any drugs.
  4. Patients with an active infection or with a fever ≥38.5oC within 3 days of the first scheduled day of dosing.
  5. Patients who had an autologous stem cell transplant within 24 months.
  6. Patients who had an available cryopreserved autologous graft with a CD34+ cell count of < 2 x 106/kg.
  7. Patients undergoing AHSCT for conditions other than lymphoma.
  8. Presence of a malignancy other than the one for which the transplant is being performed (except for baso-cellular skin carcinoma).
  9. Patients who are receiving investigational therapies or who have been treated with investigational therapies or investigational devices within 30 days prior to the first scheduled day of dosing with FE 203799.
  10. Patients with cardiovascular congestive heart failure, unstable angina pectoris, cardiac arrhythmias requiring a pacemaker; myocardial infarction within the past six months; stroke within the past 6 months; or uncontrolled hypertension.
  11. Patients with mean QTcF values of >450 msec (in males) or >470 msec (in females) following ECGs conducted in triplicate 5 minutes apart from each other; patients who are known to have congenital prolonged QT syndromes, including patients who are already on medication known to cause prolonged QT intervals on ECG.
  12. Presence of out-of-range cardiac interval (PR < 110 msec, PR > 220 msec, QRS < 60 msec, QRS >119 msec) on the screening ECG or other clinically significant ECG abnormalities.
  13. Patients with history or presence of GI tract cancer, polyps, ulcerative colitis, Crohn's disease, coeliac disease, tropical sprue, etc.
  14. Presence of active pancreatic disease.
  15. Presence of active liver disease (i.e. cirrhosis; bilirubin > ULN; transaminases > 1.5 x ULN; alkaline phosphatase > 2.5 x ULN).
  16. Presence of autoimmune disease.
  17. Patients with suicidal tendency or clinically relevant psychiatric diseases or substance abuse.
  18. Positive results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HbsAG (B) (hepatitis B)) or anti-Hepatitis C Virus (HCV (C)) tests.
  19. Any abnormal condition or laboratory result that is considered by the PI capable of altering patient's condition or study outcome.
  20. Patients who are pregnant or lactating.
  21. Patients who are unwilling to use appropriate contraception.

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): NCT03417765


Sponsors and Collaborators
GLyPharma Therapeutic
Investigators
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Principal Investigator: Silvy Lachance, MD, PhD Hôpital Maisonneuve Rosemont, Montréal, QC, Canada
Study Director: Micheline St-John, BSc JSS Research
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Responsible Party: GLyPharma Therapeutic
ClinicalTrials.gov Identifier: NCT03417765    
Other Study ID Numbers: GLY-211-2017
First Posted: January 31, 2018    Key Record Dates
Last Update Posted: October 26, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by GLyPharma Therapeutic:
gastrointestinal mucositis
myeloablative chemotherapy
autologous transplantation
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases