Neoplasms

Symptoms and General Pathology

All Conditions

Neoplasm Metastasis

Antineoplastic Agents

All Drugs and Chemicals

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Amino Acids

Trastuzumab

Bevacizumab

Atezolizumab

Alectinib

Pertuzumab

Ado-Trastuzumab Emtansine

Pralsetinib

Entrectinib

Erlotinib Hydrochloride

Vemurafenib

Adenosine

Maytansine

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immune Checkpoint Inhibitors

Tubulin Modulators

Antimitotic Agents

Immunotoxins

Immunoconjugates

Immunologic Factors

Tyrosine

If there are no drugs available under current regulation or patients are not feasible to any clinical trials, and If tumors have actionable genetic alterations and approved drug in any indications but tumor type is not indicative, the MTB may recommend one of KOSMOS-II drugs, therapeutic use of investigational products.

If there are no KOSMOS-II drugs (Tier 1) or clinical trials (Tier 3) appropriate for patients, the MTB may recommend alternative treatment options (e.g., conventional therapy, radiotherapy, or supportive care).

If patient is eligible for clinical trials matched for actionable genomic alterations found in NGS testing, the MTB will recommend enrollment to clinical trials.

ALK fusion or mutations, Mutations or amplification in any of the following: RET

MSI high status by any method Or Any mutation in any of these genes:

MLH1 or MSH2 or MSH6 or PMS2 or EPCAM Or Any of the following mutations in POLE: R150X, P286R, P286H, S297F, Y298fs, F367S, V411, L424V, P436R, S459F, R665W, L698fs, R762W, R1519C, R1826W, D316H, D316G, R409W, L474P Or Any of the following mutations in POLD1: P112fs, A930fs, S478N Or Any mutation in the following: POLE not listed above, POLD1 not listed above, POLD2, POLD3, POLD4, POLQ or PRKDC Or Any loss of function mutations in BRCA1, BRCA2, ATM, MSH3, PMS1, MLH3, EXO1, RFC1, RFC2, RFC3, RFC4, RFC5, PCNA, RPA1, PRA2, PRA3, PRA4, or SSBP1 High tumor mutational burden decided by KOSMOS-II MTB (TMB ≥20/Mb in local NGS or if 10-20/Mb, confirmed by central NGS te sting)

EGFR Exon 19 deletions in the region E746_E759;

Any of the following EGFR mutations:

E709A, E709G, E709K, E884K, G719A, G719C, G719S, L858R, L861Q, L833V, S768I

Erlotinib

ERBB2 amplification, or over-expression; or presence of any of the following ERBB2 mutations:

G309A, G309E, S310F, S310Y, R678Q, I655V, D769H, D769Y, L755S, p.L75 5_T759del, I767M, V777L, E321G, R896C; P780ins; delL755-T759 ERBB2 amplification or approved by the KOSMOS Molecular Tumor Board

Trastuzumab + Pertuzumab

ERBB2 amplification, or over-expression; or presence of any of the following ERBB2 mutations:

G309A, G309E, S310F, S310Y, R678Q, I655V, D769H, D769Y,L755S, p.L75 5_T759del, I767M, V777L, E321G, R896C; P780ins; delL755-T759 ERBB2 oncogenic mutations; G152V, X215_splice, D277Y, G292C, N302K, V308M, G309A, S310F, S310Y, S244C, L651V, V659E, G660D, R678Q, V697L, G727A, T733I, L755A, L755P, L755S, D769H, D769Y, A775_G776insSVMA, A775_G776insYVMA (i.e.,Y772_A775dup,M774_A775insAYVME 770delinsEAYVM), G776_V777 \> AVCV, G776_V777 \> AVGCV, G776_V777 \> VCV, G776_V777insVC, G776C, G776delinsLCT, G776L, G776dleinsVC, G776L777_G778insC, V777L, V777M, G778_Y779insGSP, P780_Y781insGSP (i.e.,G778_P780dup), L786V, N813D, R840W, V842I, T862A, R896G, E1021Q or approved by the KOSMOS Molecular Tumor Board

Trastuzumab emtansine

FH inactivating mutations or approved by the KOSMOS Molecular Tumor Board

Bevacizumab + Erlotinib

ROS1 gene fusion using either a fluo rescence in situ hybridization (FISH) or next-generation sequencing (NGS) or approved by the KOSMOS Molecular Tumor Board

RET fusion or mutations; CCDC6 RET, RET V804L, RET V804M, RET M918T, KIF5B-RET, RET C634W or approved by the KOSMOS Molecular Tumor Board

JEEHYUN KIM

Jina Yun

Yae-Won Yang

Keon-Uk Park

In-Hee Lee

Sung-Ae Koh

Hye-won Ryu

Yeong-ju Lee

Sang Hee Cho

Hee-Kyung Ahn

Jang-Ho Cho

So-Yeon Jeon

Gyeong-Won Lee

Seok-Jae Huh

Beo-Deul Kang

Jee Hyun Kim

Min-Hee Ryu

In-Gyu Hwang

Kyung-Eun Lee

Dong-Hoe Koo

Suk-Joong Oh

Soo-Hyeon Lee

Eunju Kang

Hyun-Ae Jung

Tae-Yong Kim

Se-Jun Park

In-Sook Woo

Min-Kyu Jung

Mi-Sun Ahn

Ho-Jung An

Hyeon-Su Im

Seung-Taek Lim

So-Yeon Oh

A national, prospective, multi-center, open-label, multi-cohort study comprised of a framework to screen patients for actionable targets and evaluation of molecular profiling guided therapy recommended by MTB based on genomic alterations using targeted and/or immunotherapies outside of the approved indications via local clinical practice (Tier 1 \& 2) and clinical trials (Tier 3)

A. The KOSMOS-II study will recruit locally advanced or metastatic solid tumor patients who had disease progression on standard first line anti-cancer treatment and/or has no standard treatment option, in order to prove MTB value to guide treatment within local clinical practice.

B. After site physicians confirm that NGS results of patients are available, they preliminarily decide initial treatment before MTB submission and collect informed consent form, and then patients can register to the KOSMOS-II study. Site physicians upload patients' clinical, pathologic, and genomic data for MTB submission. If site physician cannot determine initial treatment before MTB, site physician can record 'initial treatment cannot be determined' and can register the patient for MTB.

C. MTB records its treatment recommendations within available drugs list based on uploaded data, then site physicians make a final treatment decision, after informing patient about MTB decision and assessment of patients' final health status and preference.

D. Patients who have insufficient genomic information from their NGS results (e.g., lack of variant calling format file or uninterpretable reports) or who are candidates of immunotherapy will submit their tissue and/or blood, for central NGS testing and exploratory biomarker analysis.

E. Recommended treatment option There are three different options including (1) Tier 1: Therapeutic use of investigational products (KOSMOS-II drugs), (2) Tier 2: alternative treatment options, and (3) Tier 3: clinical trials

Patients who have insufficient genomic information from their NGS results (e.g., lack of variant calling format file or uninterpretable reports) or who are candidates of immunotherapy will submit their tissue and/or blood, for central NGS testing and exploratory biomarker analysis.

KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II

KOrean Precision Medicine Networking Group Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II

Percentage of patients who receive molecular profiling guided therapy as recommended by MTB, either in therapeutic use of investigational products (KOSMOS-II drugs), alternative treatment, or clinical trial.

Percentage of patients achieving response defined as CR/PR/SD at 16 ± 2 weeks reported by site physician

The proportion of patients who obtained CR/PR as the best response according to the RECIST 1.1 criteria

Progression-free survival in accordance with local clinical practice

The period from the start of treatment to the end of treatment for any reason

Proportion of patients alive 1 year after study registration

The incidence of serious adverse events will be calculated among the adverse events in patients with Tier 1 and Tier 3. ( based on NCI-CTCAE v5.0 )

Korean Cancer Study Group

Roche Pharma AG

Seoul National University Bundang Hospital

Professor

Digestive System Diseases

Colonic Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Micronutrients

Hematinics

Vitamins

Herbal and Botanical

Nivolumab

Leucovorin

Fluorouracil

Irinotecan

Cetuximab

Levoleucovorin

Folic Acid

Antimetabolites

Immunosuppressive Agents

Topoisomerase I Inhibitors

Folinic Acid

Folate

Vitamin B9

Cola

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

- ctDNA-POSITIVE: FOLFIRI Protocol

* FOLFIRI chemotherapy via intravenous infusion on days 1-3 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
* infusions will consist of the drugs
* 5-Fluorouracil
* Irinotecan
* Leucovorin

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

-- Active surveillance.

* Observation and monitoring with imaging (every 3 months), tumor markers, and ctDNA draws every 1 month for the initial 6 months.
* After 6 months, followed with ctDNA, tumor markers, and scans every 3 months for the first 3 years and every 6 months thereafter.

Additional scans and tumor markers will be at the discretion of the clinician. .

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

- Observation and monitoring with imaging, tumor markers, and ctDNA collections every 3 months for the first 3 years and every 6 months thereafter.

Additional scans and tumor markers will be at the discretion of the clinician

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.

If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and MSI-H, the participant will not be randomized and will be placed into the group: ctDNA positive, MSI-H: Nivolumab

-ctDNA-Positive, MSI-H: Nivolumab Protocol

* Nivolumab treatment via intravenous infusion on day 1 of each cycle. Cycle is 28 days long. This will occur for up to 12 cycles (48 weeks).
* infusions will consist of the drug Nivolumab

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.

If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and has a BRAF mutation, the participant will not be randomized and will be placed into the group: ctDNA positive, BRAF mutant: Encorafenib/Binimetinib/Cetuximab

-ctDNA-Positive, MSI-H: Encorafenib/Binimetinib/Cetuximab Protocol

* Encorafenib/Binimetinib treatment is received orally every day and Cetuximab via intravenous infusion on day 1 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
* infusions will consist of the drug Cetuximab

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. Participants that are eligible to receive Trastuzumab and Pertuzumab will be placed in this HER2 cohort: ctDNA-positive \& HER2 amplification and MSS Trastuzumab and Pertuzumab. Trastuzumab is received via intravenous administration, and Pertuzumab treatment is received intravenously by infusion. Cycle is 21 days. This will occur for up to 8 cycles.

FOLFIRI cycle will be two weeks (14 days) long, with FOLFIRI administered on Days 1-3. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of FOLFIRI chemotherapy.

FOLFIRI Protocol

Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections

ACTIVE SURVEILLANCE

Nivolumab cycle will be four weeks (28 days) long, with Nivolumab administered on day 1. Participants will receive up to 12 four-week cycles (for a total of 48 weeks) of Nivolumab treatment.

Nivolumab Protocol

Encorafenib/Binimetinib will be taken orally every day and Cetuximab will be administered intravenously on day 1 of each cycle. Cycles are 14 days long. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of Encorafenib/Binimetinib/Cetuximab.

Encorafenib/Binimetinib/Cetuximab Protocol

Trastuzumab (Herceptin) is received by intravenous administration and Pertuzumab is received intravenously by infusion on Day 1 of each cycle. Cycles are 21 days long. Participants will receive up to 8 cycles of Trastuzumab and Pertuzumab.

Aparna Parikh, MD

Rona Yaeger, MD

Manish Shah, MD

This research study is comparing two standard of care treatment options based on blood test results for participants who have metastatic colon cancer.

The names of the potential treatments involved in this study are:

* Active surveillance
* FOLFIRI treatment
* Nivolumab treatment
* Encorafenib/Binimetinib/Cetuximab treatment
* Trastuzumab + Pertuzumab

The FDA (the U.S. Food and Drug Administration) has approved FOLFIRI, comprised of Irinotecan, Leucovorin, and 5-Fluorouracil, as a treatment option for metastatic colon cancer in the Stage IV setting.

* After diagnosis and surgical removal of tumors, individuals with metastatic colon cancer commonly receive what is called adjuvant chemotherapy treatment, commonly utilizing treatment plans called FOLFOX, CAPOX, or therapy with 5-Fluorouracil.
* If all the cancer is not killed, the investigators may be able to detect tumor in the blood called circulating tumor DNA (ctDNA). This is genetic material unique to metastatic colon cancer that may be present in the blood stream, and it can be identified through a ctDNA blood test. If ctDNA is present in the blood stream, it is commonly called micro-metastatic disease (meaning disease that can't be seen detected by CT scans but may be there in the blood). Cancer researchers believe that ctDNA in the blood stream may be an indicator that cancer is more likely to recur.
* After initial adjuvant chemotherapy, it is standard for individuals to begin active surveillance, where they do not receive further treatment but instead undergo frequent tumor imaging scans to see if their cancer is stable, growing, or coming back. The investigators plan to see if additional therapy, where FOLFIRI (comprised of Irinotecan, Leucovorin, and 5-Fluorouracil) is administered can decrease recurrence. Typically, FOLFIRI is given when the disease is visibly recurrent.

  * In addition, the investigators plan to include study groups of adjuvant nivolumab treatment and adjuvant Encorafenib/Binimetinib/Cetuximab treatment to see if these treatments can decrease recurrence. The FDA has not approved either of these as a treatment options for metastatic colon cancer in the Stage IV setting.
  * Patients who have a greater than normal number of genetic markers called microsatellites are called MSI-H. Because tumor cells with these features tend to have more genetic mutations than tumor cells without them, they are more likely to be recognized by the immune system. Nivolumab is an anti-PD-1 antibody. It works by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in your immune system and controls parts of your immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus potentially allowing immune cells to recognize and destroy cancer cells.
  * Encorafenib in combination with binimetinib and cetuximab is one of the first effective regimens to target the BRAF V600E-mutation in colon cancer. When this mutation is present, it switches on pathway called the MAPK pathway which stimulates cell division and leads to uncontrolled cell growth. Encorafenib, binimetinib and cetuximab target different parts of this important signaling pathway in tumor cells with this mutation and slows down their growth and communication

However, in this research study, the investigators are

* determining whether there are differences in cancer recurrence in ctDNA positive participants treated with additional therapy versus put on active surveillance.
* determining whether there are differences in health in ctDNA positive participants treated with additional therapy versus put on active surveillance.
* examining whether patients who undergo further therapy experience changes in the ctDNA levels.

Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

Early Identification and Treatment of Occult Metastatic Disease in Stage III Colon Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research

Disease-free survival (DFS) between ctDNA-positive patients treated with additional treatment of FOLFIRI and ctDNA-positive patients who are untreated

Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated

Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2)

Determine clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort

Determine the disease-free survival (DFS) of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort

Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.

Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.

Examine the correlation of ctDNA clearance as a surrogate marker for disease burden

Compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers

Determine the DFS ctDNA-positive patients treated Herceptin/Perjeta

Determine the clearance rate of ctDNA-positive patients treated Herceptin/Perjeta

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II	NCT05525858	Solid Tumor Advanced Solid ... Metastatic Canc...	Alectinib Atezolizumab Erlotinib Trastuzumab + P... Trastuzumab emt... Vemurafenib Bevacizumab + E... Entrectinib Pralsetinib	19 Years -	Seoul National University Bundang Hospital
Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer	NCT03803553	Metastatic Colo... Stage III Colon...	FOLFIRI Protoco... ACTIVE SURVEILL... Nivolumab Proto... Encorafenib/Bin... Trastuzumab + P...	18 Years -	Massachusetts General Hospital
KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II	NCT05525858	Solid Tumor Advanced Solid ... Metastatic Canc...	Alectinib Atezolizumab Erlotinib Trastuzumab + P... Trastuzumab emt... Vemurafenib Bevacizumab + E... Entrectinib Pralsetinib	19 Years -	Seoul National University Bundang Hospital

Spots Global Cancer Trial Database for trastuzumab + pertuzumab