Neoplasms

Symptoms and General Pathology

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Neoplasm Metastasis

Carcinoma

Recurrence

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Camurati-Engelmann Disease

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Mitogens

Investigational study drug, administered intravenously every 2 weeks until disease progression or unacceptable toxicity.

PF-03446962 will be administered in 1hr intravenously at a dose of 10 mg/Kg on day 1, then every 2 weeks until the evidence of disease progression or onset of unacceptable toxicity.

PF03446962

Andrea Necchi, MD

Filippo G De Braud, MD

Alessandro M Gianni, MD

Salvage chemotherapy for advanced urothelial cancer (UC) yields suboptimal response rates of 15-40%, a median progression-free survival of 2-4 months and a median overall survival of 6 months. A rationale for targeting angiogenesis in UC is supported by preclinical evidences and early signals of clinical activity of anti-VEGF TKI as demonstrated by our group with the use of pazopanib.

Despite this activity, progression inevitably occurs and mechanisms determining resistance to conventional anti-angiogenic agents are under investigation.

PF-03446962 (Pfizer Inc) is a novel fully human monoclonal antibody (mAb) against ALK1 with dose-dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumor xenograft. The investigators suggest that PF-03446962 may increase current results for patients with advanced urothelial cancer failing upfront chemotherapy due to its mechanisms of action. Due to the lack of reliable and reproducible predictors of response as well as of imaging tools to assess tumor response, the trial will provide incorporation of 18FDG-PET/CT and contrast-enhanced ultrasound to stage and evaluate response of urothelial cancers, together with standard imaging modalities (RECIST criteria). Blood and tissue samples will be collected for translational purposes.

This is an open-label, single arm, non randomised, phase II proof-of-concept study of the monoclonal antibody against TGF-beta receptor ALK1 (PF03446962) for patients with urothelial cancer relapsing/progressing after first line chemotherapy.

The study is planned according to Simon's Optimal two-stage design. The primary endpoint is the proportion of patients who are progression-free at 2-months. A 2-month PFS rate of 50% is not promising, while a 70% rate will be promising. In stage 1, 21 evaluable patients will be accrued. If 12 patients at least will be progression-free at 2 months, enrollment will be extended to the 2nd stage for further 24 patients. If, out of the total of 45 patients, 27 at least will be progression-free at 2 months, treatment will be declared worthy for further investigations.

Maximum overall accrual is 45 patients. Type I and type II error rates will be set both at the 10% level.

PF-03446962 in Relapsed or Refractory Urothelial Cancer

Phase II Study of the Fully Human Monoclonal Antibody Against Transforming Growth Factor-beta (TGFβ) Receptor ALK1 (PF-03446962) in Relapsed or Refractory Urothelial Cancer (UC) Failing First-line Treatment.

Progression-free survival (PFS) is defined as the interval from the first dose of study drug to the date of the first documented disease progression or death for any reason, with censoring at the date of last contact for alive patients. A patient who has not progressed or died by the date of the analysis cut-off or when the patient received any further anticancer therapy would have the PFS censored at the time of last adequate tumor assessment before either cut-off date or the commencement of further anticancer therapy date, respectively.

Incidence of adverse events (AEs), defined as any new untoward medical conditions occurrence or worsening of a pre-existing medical condition that does not necessarily have a causal relationship with the study drugs. AEs will be graded according to the NCI-CTC version 4.03 and the relationship of each AEs to study drugs will be assessed by the investigator.

Assessment of response-rate by RECIST v1.1 criteria. RR (%) = CR + PR

Overall Survival (OS) will be calculated as the interval from the date of the first dose of study drug to the date of death for any cause, with censoring at the date of last contact for patients alive. The Kaplan-Meier method will be used to estimate the OS curve (median and 95% confidence interval).

Tissue will be examined in terms of genotyping by high-resolution array comparative genome hybridization (aCGH) and expression of VEGFR, PDGFR, KIT, EGFR, HER2/neu, PTEN on tissue microarrays (TMAs).

Circulating VEGF, soluble VEGFR-1, 2 and -3, soluble c-Kit, IL-6, 8, 12 and HGF will be evaluated by using multiplex ELISA plates.

Circulating tumor cells will be evaluated as a potential response biomarkers.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Principal Investigator

Wounds and Injuries

Behaviors and Mental Disorders

Hyperthermia

Fever

Body Temperature Changes

Stress Disorders, Traumatic

Heat Stress Disorders

Antineoplastic Agents

Anti-Infective Agents

Mitomycins

Mitomycin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Alkylating Agents

Enzyme Inhibitors

Pilot study single arm study to test the safety, tolerability and clinical benefit of regional hyperthermia and mitomycin-C intravesical chemotherapy to treat non-invasive Transitional Cell carcinoma (TCC) of the bladder that has recurred after standard resection and adjuvant therapy.

Hyperthermia applied to heat the bladder to a temperature of 42 degrees Celsius for 40-60 minutes concurrent with mitomycin Treatment Schedule: 6 Weekly Sessions (Induction) followed by 4 Monthly Sessions (Maintenance) until documented second recurrence

Hyperthermia System

40 mg in 40 ml sterile water instilled into bladder

Mitomycin C

Zelko Vujaskovic, MD

Brant A Inman, MD, MS

Hypothesis: In selected patients external hyperthermia will be used in combination with intravesical Mitomycin-C (MMC) to treat recurrent transitional cell carcinoma (TCC) of the bladder after local resection and standard adjuvant therapy and thus prevent or delay recurrence and the need for radical cystectomy.

It is well established that tumor cells are sensitive to heat and when combined with a chemotherapeutic agent, drug uptake and intracellular distribution of drug within malignant cells is improved due to increased cellular permeability. Further, hyperthermia inhibits deoxyribonucleic acid (DNA) repair as a result of increased reaction between DNA and chemotherapy. By heating bladder tissue and accelerating the necessary series of reactions to link agents such as mitomycin C to cell DNA, this effect may be optimized. Depending on the extent of resection (and location, size, and depth of invasion of remaining tumor) after transurethral resection of the bladder tumor(TURBT), recommended adjuvant therapy consists of intravesical chemotherapy. MMC has been studied at doses as high as 80 mg without producing significant or irreversible side effects. The most commonly used dose of mitomycin is 40 mg.2

This pilot study proposes to use Mitomycin C at a dose of 40 mg in conjunction with deep hyperthermia to enhance the effect intravesical chemotherapy as second-line treatment of recurrent TCC (Stage Ta, T1, or Tis) of the bladder after surgical resection and standard adjuvant therapy.

Mitomycin C With Hyperthermia and Intravesical Mitomycin C to Treat Recurrent Bladder Cancer

Pilot Study of External Hyperthermia and Intravesical Mitomycin-C To Treat Recurrent Bladder Cancer After Resection and Standard Adjuvant Therapy

Number of patient treatments stopped due to safety concerns or treatment intolerability. All events below are grade 1/2 toxicity. No grade 3-5 toxicity was observed.

Time to first recurrence of cancer in the bladder.

Mark Dewhirst

Professor

Mitomycin C With Hyperthermia

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Brant A. Inman, MD, MS

Pilot study single arm study to test the safety, tolerability and clinical benefit of regional hyperthermia and mitomycin-C intravesical chemotherapy to treat non-invasive Transitional Cell carcinoma (TCC) of the bladder that has recurred after standard resection and adjuvant therapy.

Hyperthermia System: Hyperthermia applied to heat the bladder to a temperature of 42 degrees Celsius for 40-60 minutes concurrent with mitomycin Treatment Schedule: 6 Weekly Sessions (Induction) followed by 4 Monthly Sessions (Maintenance) until documented second recurrence

Mitomycin C: 40 mg in 40 ml sterile water instilled into bladder

Hyperthermia System, Mitomycin C

Median Recurrence Free-survival

Abdominal pain

Fatigue

Myalgia

Heat intolerance

Urethral pain

Chemical cystitis

Hematuria

Bladder spasm

Weak urinary stream

Vaginitis

Nausea

Constipation

Swelling

Pruritis

Rash

Bruising

Flushing

Dizziness

Confusion

Anxiety

Extrapyramidal symptoms

Urinary Tract Infection

Hypertension

Safety and Tolerability

Mitomycin C with Hyperthermia to Treat Recurrent Bladder Cancer

Mitomycin C With Hyperthermia and Recurrent Bladder Cancer

Overall Study

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Breast Neoplasms

Adenocarcinoma

Triple Negative Breast Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma, Squamous Cell

Lung Neoplasms

Esophageal Squamous Cell Carcinoma

Cystadenocarcinoma, Serous

Carcinosarcoma

Mixed Tumor, Mullerian

Chromosomal Instability

Squamous Cell Carcinoma of Head and Neck

Cystadenocarcinoma

Adenoma, Pleomorphic

Endometrial Neoplasms

Neoplasms, Squamous Cell

Breast Diseases

Skin Diseases

Head and Neck Neoplasms

Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Neoplasms, Cystic, Mucinous, and Serous

Sarcoma

Neoplasms, Connective and Soft Tissue

Uterine Neoplasms

Genital Neoplasms, Female

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Chromosome Aberrations

Genomic Instability

Malignant Mixed Mullerian Tumor

Ovarian Carcinosarcoma

Uterine Carcinosarcoma

Adenocarcinoma of the Appendix

Esophageal Cancer

Soft Tissue Sarcoma

Subjects will be enrolled at various doses and/or schedules of VLS-1488. These Dose Escalation Cohorts will be utilized to identify the MTD and to select dose levels for Dose Expansion.

Additional subjects may be enrolled at any dose level that does not meet de-escalation or elimination rules per the BOIN design. These Backfill Cohorts will be utilized to build additional data to support selection of doses and/or tumor types for further study in Dose Expansion.

Subjects with a selected single tumor type will be randomized 1:1 into Exploration Cohorts at two or more dose levels of interest. A subset of subjects will have additional assessments to examine the potential for VLS-1488 to interact with other drugs and the effect of food on VLS-1488 absorption.

Subjects with other tumor types will be enrolled at a single dose level of interest. These Development Cohorts will be utilized to examine the preliminary efficacy of VLS-1488 in various tumor types.

VLS-1488

Volastra Therapeutics, Inc.

Yasmin Yazdani Farsad

Ingrid Palma

Megan Haas

Matthew Bark

Cancer AnswerLine

Abigail Van Kirk

Claire Friedman, MD

Abby Reed, RN

Emma Locke

Ecaterina Dumbrava, MD

This is a first-in-human phase I/II study to examine the safety, tolerability and preliminary efficacy of VLS-1488 in subjects with advanced cancers.

This a first-in-human phase I/II study designed to assess the safety, tolerability and preliminary efficacy of VLS-1488 monotherapy and consists of two parts: Dose Escalation and Dose Expansion.

Dose Escalation will examine the safety and tolerability of VLS-1488 in different solid tumor types at various dose levels through a series of Dose Escalation and Backfill Cohorts to identify the Maximum Tolerated Dose (MTD) and to select dose levels for Dose Expansion. The criteria for dose (de-)escalation will be based on a Bayesian Optimal Interval (BOIN) design.

Dose Expansion will examine the safety, tolerability, Drug Drug Interaction (DDI) risk, Food Effect (FE) and preliminary efficacy of VLS-1488 in different tumor types and/or dose levels of interest through various expansion cohorts.

VLS-1488 will be given orally in 28-day cycles. Dosing will be continued until disease progression, unacceptable toxicity, withdrawal of consent, or other stopping criteria are met.

A Phase I/II Study of VLS-1488 in Subjects With Advanced Cancer

A Phase I/II Study of VLS-1488 (an Oral KIF18A Inhibitor) in Subjects With Advanced Cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PF-03446962 in Relapsed or Refractory Urothelial Cancer	NCT01620970	Transitional Ce...	PF03446962	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
PF-03446962 in Relapsed or Refractory Urothelial Cancer	NCT01620970	Transitional Ce...	PF03446962	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Mitomycin C With Hyperthermia and Intravesical Mitomycin C to Treat Recurrent Bladder Cancer	NCT00734994	Transitional Ce... Superficial Bla...	Hyperthermia Sy... Mitomycin C	18 Years - 75 Years	Duke University
A Phase I/II Study of VLS-1488 in Subjects With Advanced Cancer	NCT05902988	Advanced Solid ... High Grade Sero... Squamous Non-sm... Triple Negative... Gastric Adenoca... Colorectal Aden... Esophageal Squa... Esophageal Aden... Gastroesophagea... Transitional Ce... Head and Neck S... Ovarian Carcino... Uterine Carcino... Uterine Serous ... Endometrium Can... Chromosomal Ins...	VLS-1488	18 Years -	Volastra Therapeutics, Inc.
B-Receptor Signaling in Cardiomyopathy	NCT01135849	Carcinomas Amyloidosis Anal Cancer Anemia Cholangiocarcin... Transitional Ce... Bone Marrow Tra... Bone Cancer Cancer of Brain... Breast Cancer Carcinoma of th... Endocrine Cance... Esophageal Canc... Eye Cancer Gall Bladder Ca... Gastric (Stomac... Gastrooesophage... Gastrointestina... Gynecologic Can... Head and Neck C... Hepatobiliary N... Kidney (Renal C... Leukemia Lung Cancer Hodgkin Disease Lymphoma, Non-H... Mesothelioma Multiple Myelom... Myelodysplastic... Neuroendocrine ... Myeloproliferat... Pancreatic Canc... Prostate Cancer Skin Cancer Soft Tissue Sar... Testicular Canc... Thymus Cancer Thyroid Cancer		- 40 Years	Stanford University
B-Receptor Signaling in Cardiomyopathy	NCT01135849	Carcinomas Amyloidosis Anal Cancer Anemia Cholangiocarcin... Transitional Ce... Bone Marrow Tra... Bone Cancer Cancer of Brain... Breast Cancer Carcinoma of th... Endocrine Cance... Esophageal Canc... Eye Cancer Gall Bladder Ca... Gastric (Stomac... Gastrooesophage... Gastrointestina... Gynecologic Can... Head and Neck C... Hepatobiliary N... Kidney (Renal C... Leukemia Lung Cancer Hodgkin Disease Lymphoma, Non-H... Mesothelioma Multiple Myelom... Myelodysplastic... Neuroendocrine ... Myeloproliferat... Pancreatic Canc... Prostate Cancer Skin Cancer Soft Tissue Sar... Testicular Canc... Thymus Cancer Thyroid Cancer		- 40 Years	Stanford University

Spots Global Cancer Trial Database for transitional cell carcinoma of bladder