Symptoms and General Pathology

All Conditions

Neoplasms

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Nutritional and Metabolic Diseases

Musculoskeletal Diseases

Nervous System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Syndrome

Xeroderma Pigmentosum

Cockayne Syndrome

Trichothiodystrophy Syndromes

Ichthyosis

DNA Repair-Deficiency Disorders

Congenital Abnormalities

Skin Abnormalities

Infant, Newborn, Diseases

Keratosis, Actinic

Keratosis

Skin Diseases

Precancerous Conditions

Skin Diseases, Genetic

Genetic Diseases, Inborn

Photosensitivity Disorders

Pigmentation Disorders

Metabolic Diseases

Dwarfism

Bone Diseases

Bone Diseases, Developmental

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Abnormalities, Multiple

Trichothiodystrophy

Patients who are diagnosed with a DNA Repair Disorder

Healthy family members of enrolled diagnosed participants.

The study coordinator or another team member will review standard health questions relevant to DNA repair disorders. The control group will not undergo an interval history. These questions will include:

1. How the participant's appetite and general weight trajectory has been since the last assessment
2. Any episodes of unexplained bleeding or bruising
3. Any jaundice
4. General level of alertness and interaction with family and others
5. Any changes in cognitive function such as speech, following commands, comprehension
6. Any changes in motor function, including the development of tremors and stiffness in movements

Interval History

A board-certified neurologist (the principal investigator) will perform a general physical examination and a neurological examination and complete a standard CRF to document relevant findings. The control group will not undergo a physical examination.

Physical Examination

An Early Clinical Assessment of Balance (ECAB) will be performed by the physical therapist. Part I can be assessed in all affected individuals, and Part II requires ambulation. For non-ambulatory individuals, only Part I will be applied. The items in the ECAB are summarized as follows:

Part I. Head and trunk postural control (maximum 36 points) Head righting - lateral (right and left) Head righting - extension Head righting - flexion Rotation in trunk (right and left) Equilibrium reactions in sitting (right and left) Protective extension - side Protection extension - backward Part II. Sitting and standing postural control (maximum 64 points) Sitting with back unsupported but feet supported on floor or on a stool Sitting to standing Standing unsupported with eyes closed Standing unsupported with feet together Turns 360 degrees Placing alternate foot on the step while standing unsupported

ECAB Assessment

For ambulatory participants, the physical therapist will also assess standardized gait outcome measures, including:

1. Gait Speed: may be measured over a 10 meter distance, assessing both "comfortable" walking speed and "fast" walking speed
2. 10-meter walk/run: timed assessment at fastest gait attainable. This assessment would be omitted for those participants who are determined to have a high fall risk.
3. Timed Up and Go (TUG): time to stand from a chair, walk 3 meters, go around a cone, and return to the chair (with or without an assistive device)
4. Dynamic Gait Index (DGI): assesses 8 balance challenges while walking

Gait Assessment

Total blood volumes collected at each visit will be limited to 5mL/kg body weight, with a maximum of 18mL.

Saliva samples may be obtained if research is taking place where blood samples cannot be drawn or transferred.

Specimen Sample Collection

Erin Aguero

Peter Kang, MD

Natalya Alassy, MBS

This will be a single-center, single-arm, non-interventional natural history study to evaluate the longitudinal clinical course, functional outcome measures, and candidate biomarkers for individuals with DNA repair disorders, including Cockayne syndrome (CS), xeroderma pigmentosum (XP), and trichothiodystrophy (TTD).

This will be a single-center, single-arm, non-interventional natural history study to evaluate the longitudinal clinical course, functional outcome measures, and candidate biomarkers for individuals with DNA repair disorders, including Cockayne syndrome (CS), xeroderma pigmentosum (XP), and trichothiodystrophy (TTD). Our hypothesis is that a reliable and reproducible baseline natural history course can be established for DNA repair disorders using the Early Childhood Assessment of Balance (ECAB) as a primary endpoint and other measures as secondary and exploratory endpoints that may be used in future therapeutic clinical trials.

1. Comprehensive metabolic panel (CMP) that includes electrolytes, ALT, AST, and LDH.
2. GGT
3. Bilirubin
4. Complete blood count (CBC)
5. Neurofilament light (NfL)40-42
6. Glial fibrillary acidic protein (GFAP)43
7. Total tau (t-tau)44
8. Ubiquitin C-terminal hydrolase (UCHL1)45

Natural History Study for DNA Repair Disorders

This study will be conducted in accordance with the following publication and data sharing policies and regulations: National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.

This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.

We have selected the following 4 biomarkers to be measured in serum samples at each study visit:

1. Neurofilament light (NfL)
2. Glial fibrillary acidic protein (GFAP)
3. Total tau (t-tau)
4. Ubiquitin C-terminal hydrolase (UCHL1)

We have selected the following 4 biomarkers to be measured in serum samples at each study visit:

1. Neurofilament light (NfL)40-42
2. Glial fibrillary acidic protein (GFAP)43
3. Total tau (t-tau)44
4. Ubiquitin C-terminal hydrolase (UCHL1)45 To determine whether a serum biomarker can track disease status and progression and serve as a secondary outcome measure. To determine genetic diagnoses for those who are genetically undiagnosed, and to use transcriptomic analyses to seek additional biomarker candidates.

The longitudinal stability of cerebellar and gait function will be assessed by the presence or absence of tremors (absence = 1, presence = 0), dysmetria (absence = 1, presence = 0), dysdiadochokinesia (absence = 1, presence = 0) and Gowers sign (absence = 1, presence = 0). The scores will be added to yield a total score ranging from 0 to 4, with 4 representing the best performance.

Longitudinal stability of motor function in study participants as assessed by gait speed measured over a 10 meter distance

University of Minnesota

Digestive System Diseases

Adenocarcinoma

Colonic Neoplasms

Colorectal Neoplasms

Colorectal Neoplasms, Hereditary Nonpolyposis

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Neoplastic Syndromes, Hereditary

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Bone Density Conservation Agents

Vitamins

Herbal and Botanical

Oxaliplatin

Atezolizumab

Leucovorin

Fluorouracil

Levoleucovorin

Calcium

Folic Acid

Calcium, Dietary

Vitamin B Complex

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Hormones

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Trace Elements

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Folinic Acid

Folate

Vitamin B9

Cola

Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3 of each cycle. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on day 1 of each cycle, beginning in cycle 1 or 2. Treatment repeats every 14 days for up to 25 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.

Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3 of each cycle. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.

Biospecimen Collection

Computed Tomography

Leucovorin Calcium

Magnetic Resonance Imaging

Quality-of-Life Assessment

Frank A Sinicrope

This phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer.

PRIMARY OBJECTIVE:

I. To determine whether atezolizumab combined with fluorouracil (FOLFOX) and its continuation as monotherapy can significantly improve disease-free survival (DFS) compared to FOLFOX alone in patients with stage III colon cancers and deficient DNA mismatch repair (dMMR).

SECONDARY OBJECTIVES:

I. To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve overall survival compared to FOLFOX alone in patients with stage III colon cancers and dMMR.

II. To assess the adverse events (AE) profile and safety of each treatment arm, using the Common Terminology Criteria for Adverse Events (CTCAE) and patient related outcomes (PRO)-CTCAE (among patients aged \>= 18 years).

QUALITY OF LIFE OBJECTIVE:

I. To determine the impact of the addition of atezolizumab to FOLFOX on patient-reported neuropathy, health-related quality of life (QOL), and functional domains of health-related QOL.

II. To access the efficacy of atezolizumab adjusting for baseline QOL and fatigue measurements.

POTENTIAL CORRELATIVE SCIENCE OBJECTIVES:

I. To determine if the "immunoscore" can predict the efficacy of atezolizumab for disease-free survival among patients with stage III colon cancer.

II. To assess whether circulating immune cell populations can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.

III. To explore the associations of genomic alterations identified in cell-free (cf)DNA with DFS in patients treated with FOLFOX with or without atezolizumab.

IV. To assess whether soluble markers of systemic inflammation in blood can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.

V. To assess the relationship between baseline plasma 25(OH) D levels, change in 25(OH)D levels, and DFS and overall survival (OS) in patients with stage III colon cancer receiving FOLFOX +/- atezolizumab.

VI. To determine the ability of using fecal microbiota and their metabolic products to predict survival benefit from anti-PD-L1 antibody therapy in dMMR colon cancer patients.

VII. To determine if hypermutation or hyper-indel status is associated with response to atezolizumab.

VIII. To determine if unique messenger ribonucleic acid (mRNA) expression signatures are predictive of disease-free survival among patients receiving adjuvant chemotherapy for stage III colon cancer.

IX. To determine if the efficacy of atezolizumab differs among dMMR cancers due to germline MMR mutation (MLH1, MSH2, MSH6, PMS2) versus those with MLH1 hypermethylation and CIMP in patients with stage III colon cancer.

X. To identify overall mutational burden and number of putative tumor neoantigens in colon carcinoma specimens.

XI. To determine changes in growth patterns compared to baseline (relative to age-specific standards for height and weight). (Patients aged 12 to \< 18 years to evaluate the impact of atezolizumab on growth and development patterns in this population) XII. To determine changes in development patterns compared to baseline (relative to onset of menarche \[for females\] and pubertal changes). (Patients aged 12 to \< 18 years to evaluate the impact of atezolizumab on growth and development patterns in this population)

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes starting on day 1 of cycle 1 or 2. Treatment repeats every 14 days for up to 25 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.

ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up for recurrence every 6 months for 2 years, then annually for 3 years. Patients are also followed up for survival every 6 months for up to 8 years.

Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair

Randomized Trial of Standard Chemotherapy Alone or Combined With Atezolizumab as Adjuvant Therapy for Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair

DFS will be compared between treatment arms using the stratified log rank test at one-sided level 0.025. If zero DFS events are observed in a certain stratum at an interim analysis and unstratified log-rank is used, all subsequent analyses for DFS will use unstratified log-rank test. The hazard ratio (HR) for DFS will be estimated using a stratified Cox proportional hazards model and the 95 percent confidence interval (CI) for the HR will be provided. Results from an unstratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median DFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer Crowley methodology will be used to construct the 95 percent CI for the median DFS for each treatment arm.

The distribution of overall survival will be estimated using the method of Kaplan-Meier. Overall survival will be compared between treatment arms using the log-rank test, only if DFS is statistically significant. The HR for OS will be estimated using a Cox proportional hazards model and the 95 percent CI for the HR will be provided. If a stratified log-rank test is used, stratified HR will be considered, and if an unstratified log-rank test is used, unstratified HR will be considered.

Assessed by Common Terminology Criteria for Adverse Events version 4.0. Frequency tables will be reviewed to determine the patterns. The overall adverse event rates will be compared between treatment arms using Chi-square test (or Fisher's exact test if the data in contingency table is sparse).

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Natural History Study for DNA Repair Disorders	NCT05484570	DNA Repair Diso... Cockayne Syndro... Xeroderma Pigme... Trichothiodystr...	Interval Histor... Physical Examin... ECAB Assessment Gait Assessment Specimen Sample...	6 Months -	University of Minnesota
Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair	NCT02912559	Colon Adenocarc... DNA Repair Diso... Lynch Syndrome Stage III Colon...	Atezolizumab Biospecimen Col... Computed Tomogr... Fluorouracil Leucovorin Calc... Magnetic Resona... Oxaliplatin Quality-of-Life...	12 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for dna repair disorder