APO010 starting at 2.5 µg/m² IV on D1, D15, D22 and D29 followed by a two-week drug rest.

APO010

Cristiana Sessa, Prof, MD

Two-centre, open label, uncontrolled, dose-finding phase I study, to determine the safety and tolerability of APO010 administered by intravenous bolus injection once per week. It will be the first time this agent will be administered to humans. At lower dose levels, the first cycle duration is 7 weeks. In subsequent cycles, APO010 is administered as 4 weekly doses followed by a two-week drug rest, cycle duration is 6 weeks. Based on preclinical studies of APO010 may cause liver toxicity and a drop in platelets, that recover within 5 days. The main aim of the study is to identify the recommended dose of APO010 for future clinical studies of APO010.

Two-centre, open label, uncontrolled, dose-finding phase I study, to determine the safety and tolerability of APO010 administered by intravenous bolus injection once per week in patients with solid tumors, for whom therapy of proven efficacy does not exist or is no longer effective. The dose-escalations will follow a classical Fibonacci schedule, meaning at least three patient per dose-level, prior to further escalation. The dose-level assignment and patient registration is centralized by SENDO-Switzerland \& Milan offices.

APO010, Apoxis' proprietary humanized recombinant mega-Fas-ligand, is a novel "First in class" investigational anticancer agent. APO010 is a protein that by specific binding to its cognate Fas receptor on the cell surface induces apoptosis (programmed cell death). This is called the extrinsic apoptotic pathway of cells. APO010 has shown to exert anticancer activity in vitro and in animal models carrying a human xenograft of a variety of cancers, including malignancies such as multiple myeloma, non-small cell lung cancer (NSCLC), ovarian cancer. Its activity is cell cycle independent, it does not cross react with known multi-drug resistance mechanism (MDR) and appears to be synergistic with a variety of commonly used anticancer drugs. Hence, APO010 may an attractive candidate for combination anticancer therapy and may be a effective drug in overcoming MDR.

In this study the starting dose is 2.5 microgram/m2. Normally 1/6 of the No-observed-adverse-effect level (NOAEL) dose-level in monkeys would be chosen as the first dose-level, however it has been decided to start at 25% of that dose-level. Across species (mice, rats and Cynomolgus monkeys) the rise in transaminases and drop in platelets occurred at 30 microgram/m2. The Nadir of these toxicities occurred within 6 hours and full recovery at day 5 after the bolus injection.

At the first occurrence of non-reversible (within 1 week) Common Toxicity Criteria (CTC) v3.0 Grade 2 liver function toxicity (Aspartate transaminase (AST)/Alanine transaminase (ALT) or alkaline phosphatase), i.e. Dose Limiting Toxicity (DLT), the patient accrual will be placed on hold until recovery and the subsequent timing of patient accrual to the existing and subsequent cohorts will be re-defined by the sponsor, the principal investigators and SENDO.

Pharmacokinetic assessments will be carried out in all patients during the first, and in consenting patients during the second cycles of treatment.

Assessment for immunogenicity (binding and/or neutralizing antibodies against APO010 will be carried out in all patients in all cycles of treatment before each dose and 2 weeks after the final dose.

A Phase I Dose Finding Study of APO010 in Patients With Solid Tumors

Phase I Dose Finding and Pharmacokinetic Study of Intravenous APO010, a Recombinant Form of Human Fas Ligand, in Patients With Solid Tumors

Valerio Therapeutics

Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Eye Diseases

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Rare Diseases

Carcinoma

Glioblastoma

Neuroblastoma

Sarcoma

Lung Neoplasms

Retinoblastoma

Virus Diseases

Wilms Tumor

Medulloblastoma

Sarcoma, Ewing

Carcinoid Tumor

Rhabdomyosarcoma

Rhabdomyosarcoma, Alveolar

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Soft Tissue Sarcoma

Wilms' Tumor

Ewing Sarcoma

Rhabdomyosarcoma Alveolar

Neuroendocrine Tumor

Neuroepithelioma

Dose escalation (starting at 1 × 10\^7 vp/kg), IV (in the vein) over 1 hour in a single administration

Seneca Valley Virus (biological agent)

Rudin Charles, MD, PhD

The primary purpose of the study is to determine if Seneca Valley Virus may be administered safely to patients with certain types of advanced cancer.

This is the first study in man of Seneca Valley Virus, a virus which seeks and kills certain tumors in non-human model systems. Subjects in this trial will be patients with advanced cancer displaying certain specified neuroendocrine features, pathologically; they will have exhausted standard methods of treatment for their tumor. The primary purpose of the trial is to determine if the virus may be administered safely. Additional purposes are to learn about the distribution of the virus in the body, the elimination of the virus from the body, the immune response to the virus and whether the virus might have some beneficial effects upon the tumors which the patients have. The first patients will be treated with low amounts of virus and subsequent patients may receive higher amounts. At the end of the trial, it is intended to select a dose for further study.

Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features

Phase I Dose-Escalation Study of Seneca Valley Virus (SVV-001), a Replication-Competent Picornavirus, in Patients With Advanced Solid Tumors With Neuroendocrine Features

Neotropix

Margaret Valnoski, President

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Lymphoma, Large B-Cell, Diffuse

Lymphoproliferative Disorders

Lymphoma, B-Cell

Immunoproliferative Disorders

Lymphatic Diseases

Lymphosarcoma

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Rituximab

Immunoglobulins

10 MBq/kg b.w., in escalated doses with lilotomab pre-dosing

Dose finding study, starting on 10 MBq/kg b.w. Betalutin® (lutetium (177Lu)-lilotomab satetraxetan), single injection with lilotomab pre-dosing.

Betalutin

Timothy Illidge, PhD MB BS

This study is a phase 1, dose finding, open-label study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This is a dose escalating study to define the maximum tolerated dose (MTD) of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in DLBCL patients who are not eligible for autologous stem cell transplant. The study will also assess safety and tolerability, pharmacokinetics, biodistribution and efficacy.

Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)

A Phase 1 Dose Finding Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) in Patients With Relapsed/Refractory, Diffuse Large B-cell Lymphoma, Not Eligible for Autologous Stem Cell Transplant

To determine the MTD of Betalutin that can be administered to DBLCL patients with lilotomab. The MTD was the highest dose at which less than two out of six participants experienced a dose limiting toxicity (DLT) defined as:

* Haematologic toxicity:

  * Grade 4 neutropenia observed for greater than 7 days' duration
  * Grade 4 thrombocytopenia observed for greater than 7 days' duration
  * Grade 3 or 4 neutropenia associated with fever (≥38.5°C) of any duration
  * Grade 3 or 4 thrombocytopenia with bleeding
  * Thrombocytopenia with any requirement for more than one platelet transfusion before recovering to Grade 1 or less
  * Grade 4 anaemia, unexplained by underlying disease
* Non-haematologic toxicity:

  * Grade 3 nausea/vomiting/diarrhoea lasting longer than 72 hours despite maximal care or Grade 4
  * Any other Grade 3 or 4 non-haematologic toxicities
  * Any Grade 3 or 4 electrolyte abnormalities that do not resolve to Grade 1 or baseline within 24 hours

Efficacy evaluations are measured by tumour response rates using CT and PET/CT imaging with responses classified as described in "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification" (Cheson, 2014). The Cheson criteria, 2014 are a combined score taking into consideration, positive or negative scored PET scan, the contrast enhanced CT images and bone marrow biopsies when available.

Dosimetry will be evaluated by the estimated absorbed radiation dose to target organs.

Nordic Nanovector

Treatment emergent adverse events were summarized separately after rituximab and after Betalutin/lilotomab

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 .

60/10

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2.

100/10

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 .

100/15

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0.

100/20

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Received rituximab pre-treatment on Day -14. Did not receive Betalutin or lilotomab

Rituximab Only

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

0-5 scale (5 the worst outcome) 0 Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work
2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5. Dead

ECOG score

Eligible participants who received rituximab

Head of Clinical Operations

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 pre-dosing.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing.

Number of Participants With DLTs to Determine the MTD

Participants who had a baseline and at least one post-baseline computed tomography scan

The Best Overall Tumour Response

Liver

Spleen

Kidneys

Image-based Red Marrow

Total Body

Participants having dosimetry evaluation and having the schedule of whole body imaging or SPECT/CT scans

Dosimetry

Received Rituximab

Received Lilotomab and Betalutin

Symptoms and General Pathology

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Chronic Lymphocytic Leukemia

Mantle Cell Lymphoma

Follicular Lymphoma

Marginal Zone Lymphoma

1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

Chelating Agents

Betalutin 15 MBq/kg b.w. with lilotomab pre-dosing

Betalutin 15MBq/kg b.w. with lilotomab pre-dosing

15 MBq/kg b.w. Betalutin (lutetium (177Lu) lilotomab satetraxetan) single injection, with lilotomab pre-dosing, dose 1

Betalutin with lilotomab dose 1

15 MBq/kg b.w. Betalutin (lutetium (177Lu) lilotomab satetraxetan) single injection, with lilotomab pre-dosing, dose 2

Betalutin with lilotomab dose 2

Andreas Buck, Prof. MD

This study is a phase I, open label, randomized study to assess pharmacokinetics, biodistribution and radiation dosimetry of lutetium (177Lu) lilotomab satetraxetan (Betalutin®) radioimmunotherapy in patients with relapsed non-Hodgkin lymphoma. The study will also investigate the safety, toxicity and efficacy of Betalutin and pre-dosing.

Dosimetry Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma (LYMRIT-37-02)

A Phase 1, Open Label, Randomized Study to Assess Pharmacokinetics, Biodistribution and Radiation Dosimetry of Lutetium (177Lu) Lilotomab Satetraxetan (Betalutin®) Radioimmunotherapy in Patients With Relapsed Non-Hodgkin Lymphoma

Estimation of individual tumour/organ uptake and retention of radioactivity.

Best overall response rate by treatment group as measured by Cheson Criteria.

Estimation using decay correction measurements

Nervous System Diseases

Substance Related Disorders

Neuroleptic Malignant Syndrome

Oral daily administration for 7 consecutive days every 14 days

NMS-1116354

Kyriakos Papadopoulos, MD, MSc

Bernard Laffranchi, MD

Stefania Crippa, Biotech D, PhD

The purpose of this study is to evaluate the safety profile of NMS-1116354, a CDC7 kinase inhibitor, in adult patients with advanced solid tumors.

Study of NMS-1116354 in Solid Tumors

A Phase I Dose-Escalation Study of NMS-1116354 in Adult Patients With Advanced Solid Tumors

Nerviano Medical Sciences

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

In this phase I study patients are treated with high-dose, pulsatile sorafenib in escalating AUC0-12h cohorts.

In new dosing schedule of sorafenib is investigated in this study: high-dose, pulsatile sorafenib

sorafenib

Henk MW Verheul, MD PhD

Sorafenib is an oral anticancer drug and inhibits multiple protein kinases important for tumor growth and metastases, including VEGFR, PDGFR, and RAF kinases. In daily clinical practice it is currently used at a dose of 400 mg twice daily in a continuous schedule. In this phase I study patients will be treated with a new dosing schedule of sorafenib: i.e. a high-dose, pulsatile schedule. The tolerability and safety of this new schedule is examined in exposure escalation cohorts based on a target plasma AUC0-12h (area under the curve). Exposure escalation cohorts are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.

Rationale: Preclinical research showed improved efficacy of sorafenib when given in a high-dose, pulsatile schedule compared with conventional (lower dose) continuous scheduling as a result of higher peak concentrations in the tumor. In this phase I study patients will be treated with high-dose, pulsatile sorafenib in exposure escalation cohorts. Exposure escalations cohorts are based on a target plasma AUC0-12h (area under the curve) and are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level.

Primary Objectives:

* To determine the maximum tolerated plasma AUC0-12h of high-dose sorafenib administered in a weekly, pulsatile schedule.
* To assess the safety and tolerability of high-dose, pulsatile sorafenib.

Secondary Objectives:

* To determine the pharmacokinetic behaviour of sorafenib and its major active metabolite pyridine N-oxide when administered in a weekly, pulsatile schedule.
* To determine a recommended phase II plasma AUC0-12h of high-dose sorafenib in a weekly pulsatile schedule.
* Preliminary assessment of the efficacy of high-dose, pulsatile sorafenib administered at the maximum tolerated plasma AUC0-12h.
* To determine skin and intratumoral concentrations of sorafenib and their correlation with plasma and whole blood concentrations.
* To select 1-2 optimal time points from the AUC0-12h data to determine sorafenib exposure using a finger puncture.

Study design: A single center, open-label, phase I study of high-dose, pulsatile sorafenib administered in exposure escalation cohorts.

Study population: Adult patients with locally advanced or metastatic disease for whom no standard therapy exists.

Treatment: Patients will be treated in exposure escalation cohorts with high-dose sorafenib administered in a weekly pulsatile schedule. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.

Sorafenib Administered Using a High-dose, Pulsatile Regimen: a Phase I Exposure Escalation Study

Sorafenib Administered Using a High-dose, Pulsatile Regimen in Patients With Advanced Solid Malignancies: a Phase I Exposure Escalation Study

Toxicity is graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0.

In an expansion cohort, 10 extra patients will be treated with high-dose, pulsatile sorafenib administrated at the maximum tolerated AUC. Before treatment and every 8 weeks during treatment CT thorax and abdomen will be performed and evaluated according to RECIST version 1.1.

Biopsies are only mandatory in the patients included in the expansion cohort. Concentrations are measured in biopsies using LC/MS/MS.

Finger punctures are only mandatory in de patients included in the expansion cohort. The results of the finger puncture will be compared with plasma and whole blood venous PK samples used for the AUC0-12h. The aim is to simplify full pharmacokinetic AUC sampling and to develop a method that can easily guide dose-adjustments based on sorafenib exposure.

Amsterdam UMC, location VUmc

Prof. Dr. MD PhD

Skin and Connective Tissue Diseases

Melanoma

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Vaccines

Aldesleukin

Interleukin-2

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Analgesics, Non-Narcotic

Cyclophosphamide 60 mg/kg/d by vein (IV) daily for 2 days followed by fludarabine 25 mg/m\^2 IV daily for 5 days before T cell infusion. The day after chemotherapy up to 5 x 10\^10 T cells IV infusion. Interleukin-2 90 minutes after T cell infusion at a dose of 100,000 IU/kg as IV bolus over 15 minute period every 8-hours for up to 14 doses.

Cyclophosphamide 60 mg/kg/d by vein (IV) daily for 2 days followed by fludarabine 25 mg/m\^2 IV daily for 5 days before T cell infusion. The day after chemotherapy up to 5 x 10\^10 T cells IV infusion. Interleukin-2 90 minutes after T cell infusion at a dose of 100,000 IU/kg as IV bolus over 15 minute period every 8-hours for up to 14 doses. After completion of the IL-2 treatment 3-5 doses of weekly intradermal vaccinations with up to 1.5 x 10\^7 Dendritic cells pulsed with autologous tumor lysate and NY-ESO-1 peptide.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Dose Finding Study of APO010 in Patients With Solid Tumors	NCT00437736	Cancer	APO010	18 Years -	Valerio Therapeutics
Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features	NCT00314925	Carcinoid Neuroendocrine	Seneca Valley V...	18 Years -	Neotropix
Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)	NCT02658968	Relapsed, Diffu... Refractory Diff...	Betalutin	18 Years -	Nordic Nanovector
Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)	NCT02658968	Relapsed, Diffu... Refractory Diff...	Betalutin	18 Years -	Nordic Nanovector
Dosimetry Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma (LYMRIT-37-02)	NCT02657447	Non-Hodgkin Lym...	Betalutin with ... Betalutin with ...	18 Years -	Nordic Nanovector
Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features	NCT00314925	Carcinoid Neuroendocrine	Seneca Valley V...	18 Years -	Neotropix
Study of NMS-1116354 in Solid Tumors	NCT01016327	Advanced Solid ...	NMS-1116354	18 Years - 80 Years	Nerviano Medical Sciences
A Phase I Dose Finding Study of APO010 in Patients With Solid Tumors	NCT00437736	Cancer	APO010	18 Years -	Valerio Therapeutics
Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)	NCT02658968	Relapsed, Diffu... Refractory Diff...	Betalutin	18 Years -	Nordic Nanovector
Sorafenib Administered Using a High-dose, Pulsatile Regimen: a Phase I Exposure Escalation Study	NCT02636426	Neoplasms	sorafenib	18 Years -	Amsterdam UMC, location VUmc
T Cell Transfer With or Without Dendritic Cell Vaccination in Patients With Melanoma	NCT01946373	Melanoma	Cyclophosphamid... Fludarabine T cells Interleukin-2 Dendritic cell ...	18 Years - 74 Years	Karolinska University Hospital

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