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Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation

GLP-2 analogue, once weekly, subcutaneous administration

FE 203799

Silvy Lachance, MD, PhD

Micheline St-John, BSc

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.

OUTLINE:

Multi-center, double-blind, placebo-controlled, ascending dose, randomized Phase IB/2A study to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profile of s.c. FE 203799 in patients diagnosed with Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL) undergoing Melphalan-based myeloablative chemotherapy (BEAM) followed by autologous human stem cell transplantation (AHSCT). In addition, the impact of FE 203799 on post-transplantation outcomes will be assessed. These outcomes include assessment of intestinal mucosal injury and inflammation, incidence of infection and bacteremia, development of neutropenic fever, assessment of nutritional parameters, modification of the composition of the gut microbiome, recovery of the hematopoietic system and quality of life. More specifically:

- PRIMARY OBJECTIVE: Safety and tolerability of s.c. FE 203799

- SECONDARY OBJECTIVES:

1. Determine the PK profile and dose-effect of s.c. FE 203799.
2. Determine the PD profile of s.c. FE 203799, based on the plasma concentration of citrulline (indicative of intestinal mass) and of C-Reactive Protein (CRP) (indicative of inflammation).
3. Determine the dose/response (PK/PD) relationship of s.c. FE 203799.
4. Determine the impact of treatment with s.c. FE 203799 on the incidence and severity of chemotherapy induced intestinal toxicity, as assessed by both symptomatic and visual manifestations of mucosal injury and associated complications.
5. Assess the effect of s.c. FE 203799 on the prevention of development of neutropenic fever and bacteremia.

METHODOLOGY - STUDY DESIGN The patient population will consist of adult female and male Hodgkin's or non-Hodgkin's lymphomas patients who are eligible to receive BEAM as conditioning regimen followed by autologous type AHSCT using peripheral blood or bone marrow stem cells. At the time of enrollment, patients must be in complete or partial remission following their most recent anti-neoplastic therapy. Patients are required to have available a cryopreserved autologous stem cell graft with a minimum CD34+ cell dose of 2 x 106 cells/kg.

Three ascending dose levels of FE 203799 will be investigated (5 mg, 10 mg and 25 mg), with 16 patients required per dose cohort. Patients in each dose cohort will be randomized to FE 203799 vs. Placebo in a 3:1 ratio (12 patients per dose level receiving FE 203799, and 4 patients receiving Placebo), in a double-blind manner. Randomization will occur during the screening period upon confirmation that the patient has met all inclusion and exclusion criteria. A total of 48 subjects, completing the study, is targeted for enrollment. The study will be conducted in approximately 10 clinical centers.

Eligibility will be determined at the Screening Visit following signature of the informed consent form (ICF). The inclusion and exclusion criteria will be used to qualify the patient for study entry. Within each cohort, patients will receive 4 doses of the Study Drug (FE 203799 or Placebo). As such, patients will be required to be dosed with the Study Drug the day prior the initiation of the BEAM regimen and subsequently on a weekly basis for 3 consecutive weeks after initiation of chemotherapy. Assessments performed prior to the first dose, will be considered as Baseline. Serial blood samples for determination of the plasma concentration of FE 20799/Placebo, as well as the plasma levels of citrulline and C-Reactive protein (CRP) will be obtained at pre-specified time points. During the Study, patients will be hospitalized during the duration of the conditioning chemotherapy to approximately 3 or 4 weeks post-transplantation depending on their recovery and physical condition.

All patients who received at least one treatment, will be required to return to the hospital for the End of Study Visit (Day 30 ±5 post-transplantation) and for two additional follow-up safety visits on Days 45 (±5) and 100 (±5) post-transplantation.

A Data Monitoring Committee (DMC) will convene at pre-determined timepoints, or as needed. The grading of adverse events (AEs) will be based on the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) (Grade 1 to 5).

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

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

Adverse events as assessed by CTCAE v4.03

Plasma concentration of citrulline (ng/ml)

Plasma concentration of C-Reactive Protein (ng/ml)

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

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

Assessment of duration of parenteral nutrition (L)

Determination of microbial populations by genomic analysis (relative abundance of taxonomic levels)

Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire

VectivBio AG

GlyPharma Therapeutics

Stomatitis

Gastroenteritis

Gastrointestinal Diseases

Mouth Diseases

Stomatognathic Diseases

All Drugs and Chemicals

Mitogens

Patients receive palifermin IV once daily for 3 days prior to chemotherapy and/or radiotherapy in the absence of unacceptable toxicity. Patients then receive palifermin IV on days 0, 1, and 2 after autologous or allogeneic hematopoietic stem cell transplantation.

Patients receive placebo IV once daily for 3 days prior to chemotherapy and/or radiotherapy in the absence of unacceptable toxicity. Patients then receive placebo IV on days 0, 1, and 2 after autologous or allogeneic hematopoietic stem cell transplantation.

Palifermin

Placebo

Lillian Sung

This randomized phase II trial is studying palifermin to see how well it works compared with a placebo in preventing oral mucositis caused by chemotherapy and/or radiation therapy in young patients undergoing stem cell transplant. Palifermin may help relieve or prevent oral mucositis caused by chemotherapy and radiation therapy in young patients undergoing stem cell transplant.

PRIMARY OBJECTIVES:

I. To compare whether palifermin versus placebo administered to pediatric patients three days prior to conditioning and three days after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) is associated with a reduction in the incidence of WHO grade 3 or 4 oral mucositis.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of palifermin. II. To evaluate the long-term effects of palifermin on disease outcome and survival.

III. To compare the incidence, total dose, and duration of parenteral opioid analgesic use (morphine equivalents), and incidence and duration of total parenteral nutrition (TPN) administration in patients treated with these regimens.

IV. To compare the incidence of febrile neutropenia and invasive bacterial infections in patients treated with these regimens.

TERTIARY OBJECTIVES:

I. To determine whether palifermin versus placebo reduces the incidence of WHO grade 3 or 4 oral mucositis among allogeneic HSCT pediatric patients receiving methotrexate as graft-versus-host disease (GVHD) prophylaxis.

II. To determine whether palifermin versus placebo reduces acute and chronic GVHD after allogeneic HSCT.

III. To describe health care utilization (hospitalization duration, and administration of antibiotics, TPN, nasogastric-, nasojejunal- or gastrostomy-administered enteral nutrition, and blood products) in pediatric patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to age in years (1 to 2 vs 3 to 11 vs 12 to 16), type of hematopoietic stem cell transplantation (HSCT) (autologous vs allogeneic), conditioning regimen (either total-body irradiation \[TBI\] or melphalan vs neither TBI nor melphalan). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive palifermin IV once daily for 3 days prior to chemotherapy and/or radiotherapy in the absence of unacceptable toxicity. Patients then receive palifermin IV on days 0, 1, and 2 after autologous or allogeneic HSCT.

ARM II: Patients receive placebo IV once daily for 3 days prior to chemotherapy and/or radiotherapy in the absence of unacceptable toxicity. Patients then receive placebo IV on days 0, 1, and 2 after autologous or allogeneic HSCT.

Blood samples are collected at baseline, 32 days, and 100 days after HSCT to evaluate the immunogenicity of palifermin. Oral mucositis is assessed at baseline, daily for 8 days prior to and 32 days after HSCT, or until oral mucositis has resolved by the WHO Mucositis Scale, Oral Mucositis Assessment Scale (OMAS), modified Walsh mucositis scale, Oral Mucositis Daily Questionnaire (OMDQ), and the pain categorical rating scale.

After completion of HSCT, patients are followed periodically for up to 10 years.

Palifermin in Preventing Oral Mucositis Caused by Chemotherapy and/or Radiation Therapy in Young Patients Undergoing Stem Cell Transplant

A Group-Wide Double-Blind Randomized Placebo-Controlled Trial of Palifermin to Prevent Chemotherapy and/or Radiotherapy Induced Oral Mucositis in Children Undergoing Autologous or Allogeneic Hematopoietic Stem Cell Transplantation

The incidence of WHO grade 3 or 4 mucositis, the palifermin and placebo groups, will be compared using a generalized Cochran-Mantel-Haenszel method for general association as the primary analysis. In addition, this outcome will be examined using a logistic regression model; both approaches will account for the randomization strata. Potential confounders will be examined using multiple logistic regression models.

Incidence of adverse events and laboratory abnormalities in the palifermin and placebo groups will be summarized for all study participants who receive at least one dose of study medication and also separately for autologous and allogeneic HSCT recipients using descriptive statistics. Time to neutrophil engraftment (first day of ANC 500/mm\^3 for at least 2 consecutive days) will be examined in the palifermin and placebo groups and compared using the stratified log rank test. The incidence of serum anti-palifermin antibody formation will be summarized using descriptive statistics.

Long-term outcomes (progression free survival, overall survival and second malignancies) will be examined using Kaplan-Meier and cumulative incidence curves and the compared using the stratified log rank test. These outcomes will be summarized among all study participants and also separately for autologous and allogeneic HSCT recipient.

Duration of grade 3 or 4 oral mucositis, duration of total parenteral nutrition (TPN) administration and total dose of parenteral opioid analgesic will be compared between groups using a stratified Wilcoxon test. Severity of mucositis according to the Oral Mucositis Assessment Scale (OMAS), modified Walsh mucositis scale, pain categorical rating scale and Oral Mucositis Daily Questionnaire (OMDQ) scales will be compared between groups using the area under the curve (AUC).

The AUC will be compared between groups using a stratified Wilcoxon test, in which stratum-specific rank tests are computed and then summed to obtain a combined test.

Incidence of parenteral opioid analgesic use TPN administration will be compared between groups using a generalized Cochran- Mantel-Haenszel test.

Incidence of parenteral opioid analgesic use TPN administration will be compared between groups using a generalized Cochran- Mantel-Haenszel test. If subjects are still receiving parenteral opioid analgesia or TPN on day 32, the subsequent stop date also will be collected.

The incidence of febrile neutropenia and invasive bacterial infections will be compared using a generalized Cochran-Mantel-Haenszel test.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety, Tolerability, PK/PD of FE 203799 in Adults With Lymphomas	NCT03417765	Lymphoma, Non-H... Lymphoma, Hodgk...	FE 203799	18 Years - 70 Years	VectivBio AG
Palifermin in Preventing Oral Mucositis Caused by Chemotherapy and/or Radiation Therapy in Young Patients Undergoing Stem Cell Transplant	NCT00728585	Gastrointestina... Malignant Neopl...	Palifermin Placebo	1 Year - 16 Years	Children's Oncology Group

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