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Female Urogenital Diseases and Pregnancy Complications

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Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Thiotepa

Myeloablative Chemotherapy, followed by stem cell rescue

High dose chemotherapy (carboplatin and thiotepa) transplant rescue

Myeloablative Chemotherapy

Stem Cell Rescue

John E. Levine, MS MD

The purpose of this study is to determine whether very high dosages of chemotherapy will improve the chance of surviving cancer.

This is a phase II trial designed to provide a transplant option for patients with rare poor-prognosis cancers. The protocol is only open to patients with metastatic or relapsed cancers for whom the probability of remaining free of progressive disease for one year after being brought into remission is \< 25%. Patients eligible for this study have been diagnosed with a form of cancer that leads to death more than 75% of the time when treated with standard therapy doses of chemotherapy and/ or radiation therapy. Under this treatment intensification protocol the expectation is that the one year progression-free survival for this group of patients will rise to 40%. Patients eligible for this protocol will be followed for one year post-transplant. Patients alive and free of progressive disease at the end of this period will be considered successes.

Study of High-Dose Chemotherapy With Bone Marrow or Stem Cell Transplant for Rare Poor-Prognosis Cancers

Myeloablative Chemotherapy With Stem Cell Rescue for Rare Poor-Prognosis Cancers

The primary outcome measure for this study was to improve the long-term disease-free survival of patients with rare cancers at high risk for lethal relapse.

University of Michigan Rogel Cancer Center

Professor of Pediatrics and of Internal Medicine

Myeloablative Chemotherapy: High dose chemotherapy (carboplatin and thiotepa) transplant rescue

Stem Cell Rescue: autologous stem cell transplantation

Myeloablative Chemotherapy With Stem Cell Rescue

Age, Continuous

Sex: Female, Male

Dr. John E. Levine, MD

Percent of Participants With Progression Free Survival at 1 Year

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Digestive System Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Hodgkin Disease

Mucositis

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Hodgkin Lymphoma

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

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroepithelioma

Antirheumatic Agents

Etoposide

Cyclophosphamide

Melphalan

Lenograstim

Etoposide phosphate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Adjuvants, Immunologic

Consolidation course #1 consists of thiotepa and cyclophosphamide followed by a PBSC rescue. Consolidation course #2 consists of melphalan, etoposide and carboplatin followed by a second PBSC rescue. Post infusion, patients will receive Granulocyte-Colony Stimulating Factor beginning on Day 0 of each consolidation course.

Thiotepa by IV once daily for 3 doses on Days -7, -6 and -5. Given as part of Consolidation Course #1 along with Cyclophosphamide.

Cyclophosphamide by IV once daily for 4 doses on Days -5, -4, -3 and -2. Given as part of Consolidation Course #1 along with Thiotepa.

Melphalan by IV once daily for 3 doses on Days -8, -7, and -6. Given as part of Consolidation Course #2 along with Etoposide and Carboplatin.

Etoposide by IV once daily for 4 doses on Days -8, -7, -6 and -5. Given as part of Consolidation Course #2 along with Melphalan and Carboplatin.

Carboplatin by IV once daily for 4 doses on Days -8, -7, -6 and -5. Given as part of Consolidation Course #2 along with Etoposide and Melphalan.

On Day 0 the stem cells will be infused immediately after thawing over 15-60 minutes per institutional guidelines.

Autologous Stem Cell Infusion

Beginning on day 0 after infusion of the PBSC, patients will receive G-CSF SQ or IV (SQ preferred) 5 micrograms/kg once daily and continuing once daily until post-nadir ANC \> 2000/μL for 3 consecutive days.

Granulocyte colony stimulating factor

Lisa Burke

Ashish Gupta, MBBS, MPH

Lisa Burke, RN

This is a phase II single center study to administer two courses of myeloablative consolidation chemotherapy each followed by an autologous peripheral blood stem cell (PBSC) rescue in patients with high-risk neuroblastoma who have completed induction chemotherapy (independent of this study). Ideally, patients should begin consolidation chemotherapy no later than 8 weeks after the start of Induction Cycle #5; however it is strongly recommended to begin consolidation within 4-6 weeks after the start of Induction Cycle #5.

Myeloablative Consolidation Therapy and Tandem Autologous Stem Cell Rescue in Patients With High-Risk Neuroblastoma

Tandem Myeloablative Consolidation Therapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma

Percentage of patients with progression free survial. Kaplan-Meier curves and 95% confidence intervals will be used to estimate.

Defined as an absolute neutrophil count (ANC) greater than or equal to 0.5 x 109/L for three consecutive days by day 42 after first transplant.

Percentage of patients with relapse. Relapse will be defined as any new lesion; increase of any measurable lesion by \>25%; previous negative bone is positive.

Kaplan-Meier curves and 95% confidence intervals will be used to estimate overall survival.

Masonic Cancer Center, University of Minnesota

Infections

Leukemia

Mycoses

Invasive Fungal Infections

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Hematologic Diseases

Bone Marrow Diseases

Acute Graft Versus Host Disease

Anti-Infective Agents

Clotrimazole

Miconazole

Antifungal Agents

Anidulafungin

Day 1-15: anidulafungin 200 mg q48h IV maintenance dose (8 dosages)

Day 1-13: anidulafungin 300 mg q72h IV maintenance dose (5 dosages)

anidulafungin 200 mg q48h

anidulafungin 300 mg q72h

R Brüggemann, PharmD

The purpose of this study is to study the pharmacokinetics of anidulafungin (Ecalta ®) given intravenously as antifungal prophylaxis to recipients of an allogeneic haematopoietic stem cell transplant following myeloablative chemotherapy or patients receiving intensive chemotherapy for AML-MDS who are at high risk for developing invasive fungal disease.

Alternate dosing strategies of echinocandin drugs might provide a better efficacy in the treatment of fungal infections as compared to the current label dosing strategy. Before conducting a controlled efficacy trial of echinocandins in haematology patients, the pharmacokinetics of these alternate dosing strategies need to be tested before bringing this idea to practice in a large randomised trial.

Therefore we want to conduct a pharmacokinetic study with anidulafungin given every 48 hours or every 72 hours. This research can be performed best in a group of patients at high risk for developing invasive fungal infections.

Recipients of an allogeneic haematopoietic stem cell transplant (HSCT) or patients receiving intensive chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) are at a relatively high risk of developing invasive fungal infections and are therefore candidates for primary prophylaxis. However, the options are limited to fluconazole which affords no protection against mould infections. Amphotericin B is not considered useful because of its desoxycholate formulation has too many side effects and its lipid formulations are too expensive nor have the broad-spectrum triazoles itraconazole and voriconazole proved their value in this setting. Anidulafungin is the first of a new class of antifungal drugs quite unlike any others attacking specifically the ß 1-3 -D-glucan synthase of the cell wall. It has relatively few side effects and appears safe and effective for treating Aspergillus and Candida infections. Since these two genera account for 90% of fungal infections in HSCT recipients the drug would seem an ideal candidate for prophylaxis.

Importantly, nothing is known about the pharmacokinetics of alternate dosing regimens of anidulafungin in this patient population. Therefore a pharmacokinetic study of a homogenous cohort of patients is necessary to test the assumption, that adequate exposure is obtained with alternate dosing and that it is safe.

Pharmacokinetics of Anidulafungin (Ecalta ®) Intravenous Given to Patients at High Risk for Developing Invasive Fungal Disease

Pharmacokinetics of Anidulafungin Given Intravenously as Antifungal Prophylaxis to Recipients of an Allogeneic Haematopoietic Stem Cell Transplant Following Myeloablative Chemotherapy or Patients Receiving Intensive Chemotherapy for AML-MDS

comparison of pharmacokinetics of anidulafungin given once in every two days or once in every three days

To determine whether adequate exposure is attained by patients undergoing an allogeneic haematopoietic stem cell transplant following myeloablative chemotherapy or receiving intensive chemotherapy for AML-MDS when using a q48 hour or a q72 hour dosing regimen

To determine the safety of anidulafungin in the patient population

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of High-Dose Chemotherapy With Bone Marrow or Stem Cell Transplant for Rare Poor-Prognosis Cancers	NCT00141765	Wilms Tumor Fibrosarcoma Carcinoma, Roun... Nasopharyngeal ... Brain Tumor, Re...	Myeloablative C... Stem Cell Rescu...	- 21 Years	University of Michigan Rogel Cancer Center
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
Myeloablative Consolidation Therapy and Tandem Autologous Stem Cell Rescue in Patients With High-Risk Neuroblastoma	NCT02605421	Neuroblastoma	Thiotepa Cyclophosphamid... Melphalan Etoposide Carboplatin Autologous Stem... Granulocyte col...	- 30 Years	Masonic Cancer Center, University of Minnesota
Pharmacokinetics of Anidulafungin (Ecalta ®) Intravenous Given to Patients at High Risk for Developing Invasive Fungal Disease	NCT01249820	Leukemia Myelodysplastic... Leukemia, Myelo...	anidulafungin 2... anidulafungin 3...	18 Years - 64 Years	Radboud University Medical Center

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