Neoplasms

All Conditions

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Adenocarcinoma

Neoplasm Metastasis

Endometrial Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Immunomodulating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

2-4 groups of 3 patients treatment with 200mg i.v. Pembrolizumab q3w and dose escalation of Ataluren in order to determine the Ataluren MTD. These patients can either be pMMR/dMMR CRC and dMMR EC patients.

Mismatch repair deficient CRC or EC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.

Mismatch repair proficient CRC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.

Ataluren and Pembrolizumab combination therapy

Ataluren + Pembrolizumab

Adriaan D Bins, MD PhD

Ide T Spaanderman, MD

Adriaan D. Bins, MD PhD

Punt, Prof.

Single Center, open label, Phase I-II trial designed to test the safety and efficacy of the combination of Ataluren and Pembrolizumab for the treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient endometrial carcinoma.

In controlling tumor outgrowth an intact immune surveillance is very important. PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress this immune control.

Pembrolizumab is a potent and highly selective humanized monoclonal antibody designed to directly block the interaction between PD-1 and its ligands and is registered for the treatment of advanced (unresectable or metastatic) melanoma of locally advanced or metastatic NSCLC in adults. In an earlier study it's effect has been shown in mismatch repair deficient tumors.

Ataluren is designed to allow the protein making apparatus (the ribosome) in cells to skip over a premature stop codon (PTC), allowing the cells to translate the sequence downstream of a premature termination codon (PTC) in mRNA transcripts. This may result in the translation of additional out-of-frame code, which is available in abundance in dMMR tumors. We argue that this may result in new target peptides for the immune-system to recognize cancer cells.

The investigators hypothesize that the formation of these peptides by Ataluren can enhance the effect of Pembrolizumab anti-PD1 therapy.

Therefore the investigators designed a Single Center, open label, Phase I-II trial designed to test the safety and efficacy of the combination of Ataluren and Pembrolizumab for the treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient endometrial carcinoma.

In the phase-1 part of the study 2-4 groups of 3 patients each are treated with pembrolizumab 200mg i.v. q3w but with increasing ataluren doses (i.e. group1 25%, group2 50% and group3 100% of 10-10-20mg/kg). These can be either pMMR mCRC, dMMR mCRC or dMMR EC patients. The reported toxicity in phase-1 will be used to define the maximum tolerated dose (MTD) of the combination, that will determine the ataluren dose in phase-2.

In the phase-2 part of the study a dMMR group (cohort A, 20 patients either CRC of EC) and a pMMR group (cohort B, 15 CRC patients) will be treated with pembrolizumab 200mg i.v. q3w combined with ataluren t.i.d. at the MTD defined in phase-1.

Historic case-matched controls from the MK-3475-016 study (ClinicalTrials.gov Identifier NCT01876511) and the MK-3475-177 study (ClnicalTrials.gov Identifier NCT02563002).

Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study

Study of Pembrolizumab Combined With Ataluren In Patients With Metastatic pMMR and dMMR Colorectal Adenocarcinomas or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study

mRNA and DNA sequencing measurements from normal blood, tumor, metastatic and polyp tissue: outcome measure will be mutations in DNA and RNA.

Biomarker measurements from normal blood: CEA and neoantigens (peptides)

Elispot assays from PBMCs derived from patient blood samples to check for IFN-gamma production after peptide stimulation

To characterize toxicities and side effects of Ataluren when combined with pembrolizumab in patients with pMMR CRC, dMMR mCRC and dMMR EC. Recorded on Adverse Events form and ranking adverse event severity according to the NCI Common Terminology Criteria for Adverse Events v3.0

Measured by immune-related response criteria

Historic case-matched controls from the MK-3475-016 study (ClinicalTrials.gov Identifier NCT01876511) and the MK-3475-177 study (ClnicalTrials.gov Identifier NCT02563002). Case-matching based on overall survival and immune-related response rate.

Merck Sharp & Dohme LLC

PTC Therapeutics

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

MD PhD; Principal Investigator; Oncologist

Digestive System Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Rare Diseases

Syndrome

Microsatellite Instability

Hyperplasia

Endometrial Hyperplasia

Colorectal Neoplasms

Colorectal Neoplasms, Hereditary Nonpolyposis

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Neoplastic Syndromes, Hereditary

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Genetic Diseases, Inborn

DNA Repair-Deficiency Disorders

Metabolic Diseases

Genomic Instability

Turcot Syndrome

These are patients with a diagnosis of endometrial hyperplasia at WellSpan in the study time frame diagnosed via endometrial biopsy, dilation and curettage, or hysterectomy.

Immunohistochemistry will be performed on the endometrial tissue specimens

Immunohistochemical staining

Eav Lim, DO

Given that there is a significant prevalence of Lynch syndrome among patients with endometrial cancer (about 5% of patients with endometrial cancer), and given there is a known risk of endometrial cancer among patients with endometrial hyperplasia (40% risk of pre-existing occult cancer with endometrial intraepithelial neoplasia), it is hypothesized that a diagnosis of endometrial hyperplasia may herald on-going risk of harboring a Lynch Syndrome gene mutation.

The purpose of this study is to examine endometrial hyperplasia specimens and compare the frequency of Lynch Syndrome gene mutations between endometrial hyperplasia and endometrial cancer subjects. This will provide a rationale and opportunity for earlier screening, and reduce colon cancer morbidity and mortality secondary to the Lynch syndrome gene.

This is an observational cohort study. Tissue specimens obtained that have been labeled with the diagnosis of endometrial hyperplasia will be identified and their chart reviewed for demographic date of age, race, body mass index, and co-morbidities. The specimen will then be tested via immunohistochemistry for the mismatch repair proteins MLH1, PMS2, MSH2, or MSH 6. Their absence is indicative of Lynch Syndrome. Statistical analysis will then be performed to compare the incidence of Lynch syndrome in endometrial hyperplasia with Lynch Syndrome in endometrial cancer.

No new biospecimens are retained. The biospecimens referenced are those that were already collected for tissue diagnosis of endometrial hyperplasia: endometrial biopsies, curettage specimens, and hysterectomy specimens. These are kept routinely in the pathology department on microscope slides post-procedure per hospital policy.

Frequency of Endometrial Cancer Precursors Associated With Lynch Syndrome

This is the rate of subjects who screen positive for Lynch Syndrome based on immunohistochemical staining

WellSpan Health

Principal Investigator

Colonic Neoplasms

Rectal Diseases

Herbal and Botanical

Nivolumab

Cola

Dose Escalation: To find the dose of regorafenib that can be safely given with nivolumab in patients with advanced, refractory colorectal cancers.

Dose Expansion: To find the effect on tumor of the combination of regorafenib and nivolumab.

Regorafenib orally 80 mg daily for 21 days (3 weeks on, 1 week off).

Regorafenib

Nivolumab 240 mg administered intravenously every 2 weeks.

Dae W Kim, MD

The main purpose of this study is to test the safety, tolerable side effects, and determine the highest tolerable dose of the combination of Regorafenib and Nivolumab. Researchers want to find out if this combination of Regorafenib and Nivolumab can help people with metastatic colorectal cancer with mismatch repair (MMR) proficiency.

Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer

Phase I Study of Regorafenib and Nivolumab in Mismatch Repair (MMR) Proficient Advanced Refractory Colorectal Cancer

To determine the maximum tolerated dose of Regorafenib in combination with Nivolumab in advanced, refractory colorectal cancers.

To access response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

To evaluate the frequency and severity of adverse events and tolerability of the combination regimen.

Bristol-Myers Squibb

H. Lee Moffitt Cancer Center and Research Institute

Stomach Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Stomach Cancer

MSI testing using Biocartis Idylla and MMR immunohistochemistry

Mismatch repair

Mary Jones

To compare the Idylla microsatellite instability test versus mismatch repair immunohistochemistry (IHC) in gastric adenocarcinoma.

Gastric adenocarcinoma is a common form of cancer which is associated with a poor prognosis. Up to 22% of gastric adenocarcinomas arise via the microsatellite instability (MSI) / mismatch repair (MMR) pathway. These cases can be detected either by mismatch repair immunohistochemistry (IHC) or microsatellite instability testing. Detection of mismatch repair deficiency or microsatellite instability is important because patients with this type of gastric adenocarcinoma are shown to benefit from a different therapeutic approach. High concordance between mismatch repair immunohistochemistry and microsatellite instability testing has already been demonstrated. The implementation of either method is largely based on local availability. The Idylla MSI test presents a novel method of establishing MSI status in comparison to pre-existing MSI testing platforms. The Idylla MSI tests uses a fully automated, ultra-rapid system that can work on formalin-fixed, paraffin embedded tissue with no need for preceding DNA extraction. Implementation of the Idylla MSI test could reduce reporting turnaround times and requires less technical expertise to perform in comparison to other platforms.

The investigators department does not currently have the facilities to perform MSI testing on any platform, so the advantages of introducing the Idylla MSI test would also include the generic advantages of MSI testing. These advantages include: the ability to quickly check cases shown to have possible MMR loss on IHC (i.e. equivocal cases) with MSI testing; and providing an alternative to MMR IHC for screening of Lynch syndrome, reducing the burden on reporting pathologists and reduce the inter-observer variability associated with IHC interpretation.

The Idylla MSI test already demonstrates high concordance with other MSI testing platforms but has yet to be compared to the department's accepted standard of MMR IHC. This project aims to compare the Idylla MSI test to in-house MMR IHC to establish whether the two methods are concordant in reporting MMR / MSI status in gastric adenocarcinoma.

A Retrospective Validations Microsatellite Instability (MSI) Testing v Mismatch Repair (MMR) in Gastric Adenocarcinoma

A Retrospective Validation of Idylla Microsatellite Instability Testing Versus Mismatch Repair Immunohistochemistry in Gastric Adenocarcinoma Biopsies

MMR IHC panels will be passed to the histopathology team for interpretation. Cases will be interpreted and results will be determined by either a) loss of staining or b) no loss of staining of any individual antibody

Royal Cornwall Hospitals Trust

Use next-generation sequencing to test germline mutation and microsatellite instability.

next-generation sequencing

Ying Yuan, MD

The purpose of this study is to determine the proportion of patients diagnosed with Lynch syndrome in colorectal cancer patients with the loss of staining by immunohistochemistry (IHC) of any of the mismatch repair (MMR) proteins. Besides, this study aims to test the specificity and the sensitivity of detecting microsatellite instability (MSI) by next-generation sequencing, and to find out the consistency between IHC and MSI in colorectal cancer patients in China. In addition, researchers want to analyze the clinical characteristics and germline mutation of Lynch syndrome in Chinese population.

1. Detect microsatellite instability (by next-generation sequencing and PCR capillary electrophoresis) and germline mutation (by next-generation sequencing) in probands.
2. Analyze the test outcome with clinical and family information to evaluate the germline mutation status preliminarily: likely pathogenic germline mutation, variant of uncertain significance, non-pathogenic germline mutation.
3. Verify the germline mutation in blood relatives whose proband has known likely pathogenic germline mutation or variant of uncertain significance.
4. Diagnose pathogenic germline mutation and non-pathogenic germline mutation based on clinical characteristics, family information and germline mutation test outcomes (including the outcomes of probands and blood relatives). Diagnose Lynch syndrome and the pathogenic germline mutation carriers in the included population.
5. Analyze the specificity and the sensitivity of detecting microsatellite instability (MSI) by next-generation sequencing; and analyze the consistency between IHC and MSI.
6. Analyze the clinical characteristics and germline mutation of Lynch syndrome in Chinese population.

whole blood, frozen tissue, paraffin tissue, Formalin-fixed tissue and RNA-later preserved tissue.

Diagnosis of Lynch Syndrome Based on Next-generation Sequencing in Colorectal Cancer

Diagnosis of Lynch Syndrome Based on the Colorectal Core™ Platform in Colorectal Cancer Patients With the Loss of Staining by Immunohistochemistry (IHC) of Any of the Mismatch Repair (MMR) Proteins: An Open-label and Multi-center Study

Pathogenic germline mutation using next-generation sequencing with a targeted panel.

Variant of uncertain significance of germline mutation using next-generation sequencing with a targeted panel.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study	NCT04014530	Colorectal Canc... Endometrium Can...	Ataluren + Pemb...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study	NCT04014530	Colorectal Canc... Endometrium Can...	Ataluren + Pemb...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Frequency of Endometrial Cancer Precursors Associated With Lynch Syndrome	NCT05257057	Lynch Syndrome Endometrial Can... Endometrial Hyp... Mismatch Repair... Microsatellite ...	Immunohistochem...	18 Years - 99 Years	WellSpan Health
Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer	NCT03712943	Colorectal Canc... Metastatic Colo... Colon Cancer	Regorafenib Nivolumab	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
A Retrospective Validations Microsatellite Instability (MSI) Testing v Mismatch Repair (MMR) in Gastric Adenocarcinoma	NCT04232020	Gastric Cancer	Mismatch repair	-	Royal Cornwall Hospitals Trust
Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer	NCT03712943	Colorectal Canc... Metastatic Colo... Colon Cancer	Regorafenib Nivolumab	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study	NCT04014530	Colorectal Canc... Endometrium Can...	Ataluren + Pemb...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Frequency of Endometrial Cancer Precursors Associated With Lynch Syndrome	NCT05257057	Lynch Syndrome Endometrial Can... Endometrial Hyp... Mismatch Repair... Microsatellite ...	Immunohistochem...	18 Years - 99 Years	WellSpan Health
Diagnosis of Lynch Syndrome Based on Next-generation Sequencing in Colorectal Cancer	NCT03047226	Lynch Syndrome	next-generation...	-	Second Affiliated Hospital, School of Medicine, Zhejiang University

Spots Global Cancer Trial Database for mismatch repair