Gastrointestinal Cancer

1. Cohort A and B: T1-3, N1/N1c
2. Pathologic stages II or IIIC w/commercially obtained Signatera ctDNA+ve assay are eligible for enrollment and inclusion in Cohort B
3. Ro resection
4. Consented and randomized < 60 days from surgical resection

T1-2N0 and must be able to a TEMS candidate with surgery

- Histologically confirmed invasive, well-moderately differentiated rectal adenocarcinoma,
mismatch repair proficient.

- MRI stage:
a) cT1 not eligible for transanal surgery alone as per NCCN guidelines, (including but not limited
to T1 tumours >2 cm in size, positive margin, tumour depth SM3 invasion to the lower third of the
submucosal level).
or
b) cT2


- cN0 stage based on pelvic MRI – including absence of radiographic evidence of mesorectal nodal
metastasis, tumour deposits or extramural venous invasion (EMVI).

- M0 stage based on no evidence of metastatic disease by CT imaging of chest, abdomen and pelvis.

- Mid to low-lying tumour eligible for transanal excision in the opinion of the treating surgeon.

- Medically fit to undergo radical TME surgery as per treating surgeon’s decision

*Patient must be ≥ 18 years of age.
*Patient must have confirmed unresectable liver confined metastatic colorectal cancer (CRC).
*Patient must not have radiographically or clinically evident extrahepatic disease (including but not limited to radiographically positive periportal lymph nodes).
*Patient must have received previous first-line chemotherapy that meets one of the following three criteria: a) have received at least 6 but no more than 12 cycles of first-line cytotoxic chemotherapy (where ECOG-ACRIN EA2222 Cancer Research Group Version Date: November 27, 2024 14 1 cycle = 14 days) OR b) have received at least 4 but no more than 8 cycles of first-line cytotoxic chemotherapy (where 1 cycle = 21 days) OR c) have developed new colorectal liver metastases (CRLM) within 12 months of completing adjuvant systemic therapy for stage II-III colorectal cancer.

Age ≥18 years. Because no dosing or adverse event data are currently available on the use of CA-4948 (emavusertib) and FOLFOX in combination with bevacizumab in patients < Grade 2 (CPK ≤ 2.5 x ULN)

Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start.

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)–directed therapy shows no evidence of progression.
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible, after discussion with the PI or medical monitor, if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first cycle of therapy.

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better.

Inclusion:
2. Histological or cytological confirmed colorectal adenocarcinoma.
3. Evidence of Stage IV metastatic disease.
4. Known RAS mutation status per local test (includes KRAS and NRAS exons 2,3 and 4 codons 12, 13, 59, 61, 117 and 146). Participants with unknown RAS status despite attempt to test are eligible for participation.
5. No prior systemic therapy for metastatic disease.
Note: Participants with early-stage disease who received prior systemic neoadjuvant or adjuvant chemotherapy and present with reoccurrence/metastatic disease within 6 months of stopping treatment will count as having prior therapy in the metastatic setting and are not eligible.


Exclusion:
1. Locally confirmed BRAF V600E mutation
2. Locally confirmed MSI-high or dMMR colorectal cancer
3. Participants with known active symptomatic CNS lesions, including leptomeningeal metastasis, brainstem, meningeal, or spinal cord metastases or compression Note: Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be enrolled if all of the following are met:
a. CNS metastases have been clinically stable with no evidence of clinical or radiographic disease progression for ≥14 days after completion of definitive radiotherapy and/or surgery and prior to study intervention.
b. The participant has not required steroids for brain metastasis symptom management for 7 days prior to first dose of study intervention.
4. Known DPD deficiency (refer to the local 5-FU label or local clinical guidance for DPD status recommendation prior to starting treatment)

* Have histologically or cytologically confirmed adenocarcinoma of the colon or rectum.

* Participants must have recurrent, unresectable or metastatic disease.
Note:
 Carcinoma of the anal canal is excluded.

* Be diagnosed to have KRAS, NRAS, and BRAF WT tumor as determined by local testing.
Both tissue- and blood-based testing is an acceptable method for the eligibility
determination.
The local test must at least include and participants must be WT for KRAS/NRAS G12 and
G13 and BRAF V600 codons. Other KRAS/NRAS codons, as well as MSI-H/dMMR status
and ERBB2/HER2 amplification status, should be determined per the local guidelines and
standard practice. A participant is excluded from the study if the participant is known to
have a mutation (with the exception of a silent mutation) in any of the following codons
based on local testing: KRAS/NRAS G12, G13, A59, Q61, K117, or A146 or BRAF V600.

A copy of the test report documenting the WT status for KRAS/NRAS and BRAF must be
included in the participant records, and a de-identified copy must be submitted to the
sponsor during the screening period.

The local test must be performed prior to randomization in accordance with local
guidelines using an FDA-approved test or laboratory-developed test that is validated in a
CLIA-certified laboratory (sites in the United States) or an accredited local laboratory
(sites outside of the United States). In the European Union, the local test must be
CE-marked or an in-house laboratory-developed test from health institutions in the
European Union in accordance with Article 5(5) of the IVDR 2071/746, as amended.

* Must agree to the submission of fresh or archival tumor tissue post-progression from the
most recent therapy, if clinically feasible.

Prior Therapy Restrictions or Requirements
* Participant must have received 1 line of systemic therapy for mCRC, with documented
radiographic disease progression on or after this line of therapy. The regimen must be
fluoropyrimidine-based and oxaliplatin-based therapy. Prior anti-VEGF therapy is
allowed according to local regulatory approvals and SoC guidelines.
Note:
 Definition of 1 line of therapy equates to disease progression from 1 and only 1 prior
regimen for mCRC.
 Rechallenge of a same regimen after disease progression or maintenance therapy will
not count as an additional line of therapy.
 Recurrence from prior neoadjuvant/adjuvant chemotherapy <12 months from the last
course of systemic chemotherapy is considered as 1 prior line in the metastatic setting
and, with this 1 line, the participant will be eligible for the study

Key eligibility criteria:

Inclusion criteria:
2. Male or female aged ≥18 years.
3. Presence of histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS status for each participant must be documented.
4. Have been previously treated with standard approved therapies:
– Fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy,
– An anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab [regorafenib is NOT an anti-VEGF biologic]),
– If RAS wild-type and medically appropriate, an anti-EGFR therapy (eg, cetuximab, panitumumab), and
– If known MSI-H or dMMR tumor and medically appropriate, a programmed cell death protein 1 (PD1) inhibitor.
5. Self-identify as Black and/or African American or Hispanic and/or Latino or as both.
6. Body weight ≥40 kg.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at screening (Table 16.a, Section 16.1).
8. Have assessable disease according to RECIST version 1.1 (Section 16.2), assessed locally.


Exclusion criteria:
Individuals who meet any of the following criteria will be excluded from participation in this trial:
1.Absolute neutrophil count (ANC) 1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin 2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
2. Serum total bilirubin >1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin
3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
4. Creatinine clearance <30ml/min Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation (see Section 8.3.4.2). Where available and appropriate, other formulae may be used to estimate clearance after consultation with the trial medical monitor.
5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24 hours. Participants with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
6. Uncontrolled hypertension, defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg despite optimal medical management. The participant must have BP below both limits. Repeated assessments are permitted.
7. International normalized ratio (INR) >1.5 × ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the participant is currently receiving or intended to receive anticoagulants for prophylactic purposes.
8. History of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas, or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation within the 6 months prior to screening.
9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening.
10. History of a thromboembolic event, including deep vein thrombosis, pulmonary embolism, or arterial embolism within 6 months prior to screening.
11. Stroke and/or transient ischemic attack within 12 months prior to screening.
12. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction 480 milliseconds or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrom

Key eligibility criteria:

Inclusion criteria:
2. Male or female aged ≥18 years.
3. Presence of histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS status for each participant must be documented.
4. Have been previously treated with standard approved therapies:
– Fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy,
– An anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab [regorafenib is NOT an anti-VEGF biologic]),
– If RAS wild-type and medically appropriate, an anti-EGFR therapy (eg, cetuximab, panitumumab), and
– If known MSI-H or dMMR tumor and medically appropriate, a programmed cell death protein 1 (PD1) inhibitor.
5. Self-identify as Black and/or African American or Hispanic and/or Latino or as both.
6. Body weight ≥40 kg.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at screening (Table 16.a, Section 16.1).
8. Have assessable disease according to RECIST version 1.1 (Section 16.2), assessed locally.


Exclusion criteria:
Individuals who meet any of the following criteria will be excluded from participation in this trial:
1.Absolute neutrophil count (ANC) 1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin 2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
2. Serum total bilirubin >1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin
3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
4. Creatinine clearance <30ml/min Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation (see Section 8.3.4.2). Where available and appropriate, other formulae may be used to estimate clearance after consultation with the trial medical monitor.
5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24 hours. Participants with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
6. Uncontrolled hypertension, defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg despite optimal medical management. The participant must have BP below both limits. Repeated assessments are permitted.
7. International normalized ratio (INR) >1.5 × ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the participant is currently receiving or intended to receive anticoagulants for prophylactic purposes.
8. History of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas, or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation within the 6 months prior to screening.
9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening.
10. History of a thromboembolic event, including deep vein thrombosis, pulmonary embolism, or arterial embolism within 6 months prior to screening.
11. Stroke and/or transient ischemic attack within 12 months prior to screening.
12. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction 480 milliseconds or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrom

Cohort B5 is for ATM negative CRC (tested centrally) for 3rd line use with irinotecan plus IP; they don’t count targeted therapies as a line of therapy so anticipate people would have had 5fu, oxaliplatin and irinotecan already, so can add to the metastatic colorectal cancer flowsheet with the 3rd line and above studies

Cohort B6 is for ATM low pancreas adenocarcinoma and would highlight this also includes acinar cell carcinomas, max of 1 prior line of therapy combined with irinotecan, so can put on the Refractory column of the Pancreas flowsheet

Key Eligibility Criteria:
Inclusion Criteria:
1. Males or females aged >/= 12 to less than 85 years for Ewing sarcoma and 18 to less than 85 years of age for other tumors.
2. Part 3 combination therapy expansion tumor types:
- Histologically confirmed Ewing sarcoma with a classical fusion: Patients with locally advanced or metastatic, unresectable, relapsed, or refractory disease who have received at least 1 but no more than 2 prior lines of systemic treatment with a preferred first line chemotherapy regimens.
- Colorectal adenocarcinoma: Patients with locally advanced or metastatic, unresectable disease, who have received at least 2 but no more than 3 prior lines of systemic therapy.
3. Availability of archival tissue or fresh cancer biopsy are mandatory.

Exclusion Criteria:
1. Prior treatment with or exposure to DR5 agonists.
2. Receipt of any anticancer therapy (including investigational agents) within 4 weeks or within 5 half-lives prior to the first dose of study treatment. Exceptions per protocol.
3. Allergy or sensitivity to INBRX-109 or known allergies to CHO-produced antibodies.
4. Receipt of radiotherapy within 4 weeks prior to the first dose of study treatment, and liver-directed within 12 months prior to the first dose of study drug.

For pre-screening, please contact: Message Basket: VICC RESEARCH REFERRALS/ELIGIBILITY

Key Eligibility Criteria:
Inclusion:
1. Dose Escalation additional criteria: Patients must have histologically confirmed cancer that is metastatic or unresectable and must have progressed on standard therapies which would have included fluorouracil (5-FU) or capecitabine
2. Dose Escalation additional criteria specifically for colorectal cancer (CRC) patients: Willingness and ability to undergo a pre-treatment biopsy
3. Dose Expansion additional criteria: Patients must have histologically confirmed CRC that is metastatic or unresectable and must have progressed on standard therapies which would have included 5-FU or capecitabine
4. Dose Expansion additional criteria: Willingness and ability to undergo pre- and on- treatment biopsies

Exclusion:
1. Previous treatment with BET inhibitors
2. History of inability to tolerate capecitabine at the projected treatment dose on this trial
3. Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
4. Hepatic tumor burden > 30% or peritoneal carcinomatosis

For pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1

Cohort B5 is for ATM negative CRC (tested centrally) for 3rd line use with irinotecan plus IP; they don’t count targeted therapies as a line of therapy so anticipate people would have had 5fu, oxaliplatin and irinotecan already, so can add to the metastatic colorectal cancer flowsheet with the 3rd line and above studies

Cohort B6 is for ATM low pancreas adenocarcinoma and would highlight this also includes acinar cell carcinomas, max of 1 prior line of therapy combined with irinotecan, so can put on the Refractory column of the Pancreas flowsheet

Key Eligibility Criteria:
Inclusion:
1. Dose Escalation additional criteria: Patients must have histologically confirmed cancer that is metastatic or unresectable and must have progressed on standard therapies which would have included fluorouracil (5-FU) or capecitabine
2. Dose Escalation additional criteria specifically for colorectal cancer (CRC) patients: Willingness and ability to undergo a pre-treatment biopsy
3. Dose Expansion additional criteria: Patients must have histologically confirmed CRC that is metastatic or unresectable and must have progressed on standard therapies which would have included 5-FU or capecitabine
4. Dose Expansion additional criteria: Willingness and ability to undergo pre- and on- treatment biopsies

Exclusion:
1. Previous treatment with BET inhibitors
2. History of inability to tolerate capecitabine at the projected treatment dose on this trial
3. Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
4. Hepatic tumor burden > 30% or peritoneal carcinomatosis

For pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1

Key Eligibility Criteria:

Inclusion Criteria:
1. Histologically documented locally advanced and unresectable or metastatic NSCLC, PDAC, CRC, or other solid tumor with KRAS G12A, G12C, G12D, G12S, or G12V mutation
2. Measurable disease by RECIST v1.1
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Exclusion Criteria:
1. Malignancy within the last 2 years as specified in the protocol
2. Untreated brain metastases
3. Known hypersensitivity to BBO-11818 or its excipients

For pre-screening, please contact: VICC RESEARCH PHASE 1

Eligibility Criteria
Inclusion Criteria:
1. Single agent BCA101 - patients with the following tumor type will be eligible:
a. No prior history of treatment with anti-EGFR antibodies in the unresectable/metastatic setting (prior treatment with radiotherapy in the adjuvant setting is allowed).
2. Combination BCA101 and pembrolizumab - patients with the following tumor types will be eligible:
a. Patients must have no prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy completed >6 months prior if given as part of multimodal treatment for locally advanced disease) or prior history of immune checkpoint inhibitors with the exception of neoadjuvant therapy (>6 months prior to study drug initiation). No prior history of anti-EGFR antibodies (with the exception of radiosensitizing agents and multimodal treatment for locally advanced disease).
b. Patients must provide tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient): A newly obtained biopsy (within 90 days prior to start of study treatment) is preferred but an archival sample is acceptable.
c. Patients must have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer
d. Patients must have progressed on one prior systemic therapy in the metastatic setting.
e. No prior history of treatment with anti-EGFR antibodies in the metastatic setting.
f. Expansion Cohort 6: Head and Neck Squamous Cell Carcinoma (HNSCC), metastatic or unresectable, recurrent with a Combined Positive Score (CPS) less than 1, as determined by PD-L1 IHC 22C3 pharmDx.
3. Randomized to either ficerafusp alfa alone or in combination with pembrolizumab -Expansion Cohort 9: Colorectal cancer (CRC) i. Patients must have received at least 2 and no more than 3 prior lines of systemic therapy including two standard treatment regimens.

Exclusion Criteria:
1. Prior treatment with any anti-TGFb therapy.
2. Has a history of (non-infectious) pneumonitis, radiation pneumonitis or interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.

For pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1

Drug(s)/Mechanism:
Belzutifan

Eligiblity information:
Cohort B1 specific inclusion criteria:

1. Have a diagnosis of VHL disease as determined by a germline test (documented germline VHL gene alteration) locally and/or clinical diagnosis, which can be made in the
following instances:
a. in a participant with a family history of VHL disease and at least one of the characteristic VHL-related tumors (eg, retinal HBs, CNS HBs, clear cell RCCs, pNETs, and endolymphatic sac tumors).
b. in the presence of 2 or more retinal or CNS HBs.
c. in the presence of 1 retinal or CNS HB, plus at least 1 of the characteristic VHLrelated visceral tumors, excluding renal and epididymal cysts.

2. Have at least 1 measurable PPGL or pNET per RECIST 1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified by BICR. BICR must verify the
presence of radiologically measurable disease per RECIST 1.1 for either PPGL or pNET for the participant to be eligible for the study.

3. For Cohort B1 participants with PPGL:
a. No pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate surgery.
b. Participants should have adequately controlled BP defined as BP 150/90 mm Hg and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment.
c. Metastatic or locally advanced, unresectable PPGL will be exclusionary.
d. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

4. For Cohort B1 participants with pNET:
a. No lesion(s) located in the head of the pancreas must be >2 cm that requires immediate surgery.
b. No lesion(s) located in the body or tail of the pancreas must be >3 cm that requires immediate surgery.
c. Locally advanced, unresectable or metastatic pNET will be exclusionary.
d. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

5. For Cohort B1 participants with RCC:
a. No lesion(s) must be >3 cm that requires immediate surgery.
b. Metastatic RCC will be exclusionary.
c. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

6. For Cohort D participants with advanced solid tumors with HIF-2A related genetic alterations:
a. Local test report documenting germline or somatic mutations in at least one of the HIF-2A related genes (HIF-2A/EPAS1, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, EGLN1, EGLN2, MDH2, ELOC/TCEB1).
b. Has locally advanced or metastatic solid tumor that is not amenable to surgery or curative intent treatment.
c. Participants must have progressed on/after standard therapy for advanced/metastatic disease. More than 3 prior therapies will not be allowed for this cohort in the advanced/metastatic setting.

For pre-screening, please contact: Message Basket: VICC RESEARCH REFERRALS/ELIGIBILITY

Inclusion Criteria:
1. Participants must have histologically-confirmed (local site pathological confirmation sufficient) extrapulmonary poorly differentiated, neuroendocrine carcinoma (NEC).
2. Participants must have disease that is unresectable or metastatic and not eligible for definitive therapy as deemed per the treating investigator.
3. Participants with prior history of non-metastatic (localized/locally advanced disease) extrapulmonary poorly differentiated NEC may have had prior platinumbased therapy +/- radiation +/- surgery provided that all therapy was completed >/= 6 months prior to registration.
4. Participants must not have had prior treatment for advanced or metastatic NEC EXCEPT one cycle of platinum (carboplatin/cisplatin) + etoposide is allowed prior to registration. Other chemotherapy regimens are not allowed. For participants with prostate or urothelial NEC, prior chemotherapy for the non-NEC component (e.g. adenocarcinoma or urothelial) is allowed as long as such therapy was completed >/= 24 weeks prior to registration and participants have recovered from all prior toxicities to </= grade 1.
5. Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, antiPD-L2, CD137 agonists, anti-CTLA-4 agent, or any other immune checkpoint inhibitors for any neuroendocrine neoplasm. Immune checkpoint inhibitors given for other cancer indications are allowed provided last therapy was given at least
12 months prior to study registration.

Key Eligibility Criteria:

Inclusion Criteria:
1. Must meet the following:
a) Newly diagnosed metastatic or unresectable locally advanced (i.e., surgery with curative intent is not an option) colorectal adenocarcinoma and about to start first line chemotherapy. Patients must not have relapsed within 6 months after completing prior treatment for early-stage disease.
b) Determined by the Investigator to be ready to receive their second dose of chemotherapy.
c) If currently participating in the clinical trial under the original protocol and the patient is willing to continue the study drug for a maximum total of 12-weeks of study drug treatment once Amendment #1 is IRB / IEC approved, the updated consent has been signed during the patient’s participation, and the patient is still receiving study drug treatment as part of the 28-day study.
2. Starting chemotherapy routines allowed are: FOLFOX, FOLFIRI, or FOLFIRINOX with or without bevacizumab, or other monoclonals or other FDA approved agents to be dosed every 2 weeks. The primary cancer therapy (dose, schedule, or drugs) may be changed as medically indicated.
3. Must have a BMI ≤ 33 kg/m2.
4. Must be able and willing to safely self-inject daily or be injected by a caregiver.
5. Able to eat and digest food normally. Patients with colostomies are allowed.

Exclusion Criteria:
1. Patients receiving second line or later systemic treatment .
2. History of weight loss surgery including gastric stapling, or bypass surgery.
3. Unintentional weight loss ≥ 10% of usual body weight in 4 months prior to Screening or other weight loss considered significant by the Investigator.
4. Currently using any new agent designed to increase appetite or otherwise affect weight (increase or decrease). Antiemetics to control nausea are acceptable.
5. History of bulimia or anorexia.

For internal pre-screening, please contact:
Epic message basket- Reach out to the disease specific research team.

Key Eligibility Criteria:

Inclusion:
1. < 40 years of age at the time of enrollment
2. Patient must be a post-menarchal female and report that their initial menstrual period occurred > 6 months prior to enrollment. (Current menstrual status is not part of the inclusion criteria.)
3. Newly diagnosed with first cancer, exclusive of breast cancer.
4. Planned treatment must include one or more of the following alkylating agents delivered with curative intent: cyclophosphamide, ifosfamide, procarbazine, chlorambucil, carmustine (BCNU), lomustine (CCNU), melphalan, thiotepa, busulfan, nitrogen mustard.
5. For patients < 20 years of age at enrollment, the expected alkylator dose must be ≥ 4 g/m^2 cumulative cyclophosphamide equivalent dose (CED). For patients ≥ 20 years of age at enrollment, any planned alkylator dose is permitted. Eligible patients must receive at least one of the alkylators that contribute to CED.

Exclusion:
1. Any planned radiation to the pelvis; or cranial radiation ≥ 30 gray (Gy) to the hypothalamus, inclusive of any total body irradiation (TBI).
2. Planned bilateral oophorectomy. Note: A participant's desire to pursue alternative fertility preservation procedures (i.e., embryo, oocyte, or ovarian tissue cryopreservation) will be allowed (and in fact encouraged).
3. Receipt of long acting (depot) GnRH agonists within 6 months before enrollment. In contrast, subcutaneous GnRH agonist used for oocyte retrieval is not an exclusion; oral and other hormonal contraceptive use is also not an exclusion. Note: Please see protocol for the concomitant therapy restrictions for patients during the study treatment period. See protocol for information about oral and other hormonal contractive use during the study treatment period.
4. Prior receipt of systemic chemotherapy. However, steroids and intrathecal chemotherapy are permitted prior to study enrollment.
5. Any prior radiation to the pelvis; or cranial radiation ≥ 30 Gy to the hypothalamus, inclusive of any total body irradiation (TBI).

For pre-screening, please contact: Please reach out to the Disease specific research teams.

Key Eligibility Criteria:

Inclusion Criteria:
1. Planned intravenous treatment with a minimum of 12 weeks of neurotoxic chemotherapy treatment and with no planned treatment pause for surgery during neurotoxic chemotherapy treatment.
a. With one of the following treatments:
i. Chemotherapy regimens based on Oxaliplatin
1. FOLFOX every 2 weeks
2. FOLFIRINOX every 2 weeks
ii. Chemotherapy regimens based on single-agent Paclitaxel
1. Paclitaxel weekly
2. Paclitaxel every 3 weeks
iii. Chemotherapy regimens based on Paclitaxel + Carboplatin
1. Paclitaxel weekly with Carboplatin weekly/every 3 weeks
2. Paclitaxel every 3 weeks with Carboplatin every 3 weeks
b. Concurrent administration of the chemotherapies listed in the inclusion criteria with or without targeted agents/immunotherapy at standard doses is allowed (such as trastuzumab, pertuzumab, bevacizumab, pembrolizumab or other immune checkpoint inhibitors).
2. Planned taxane or platinum containing portion of chemotherapy regimen prescribed to last at least 12 weeks in duration and less than or equal to 12 months in duration. Note: The regimen is prescribed as per physician discretion in accordance with standard of care guidelines.

Exclusion Criteria:
1. Baseline peripheral neuropathy of any kind as defined by NCI CTCAE v5.0 grade > 0.
2. Any open wounds, sores, cysts or injury on the participant's hand or on part of the upper arm where the device will be applied or on the participant's feet or part of the lower leg where the device will be applied, which in the opinion of the investigator will not be healed prior to infusion commencing or who in the opinion of the investigator will be inappropriate for inclusion in this study.
3. Weight greater than 140 kg at the time of enrollment.
4. Participants who are receiving neuropathy directed systemic therapies at the time of enrollment, namely, Pregabalin, Gabapentin, Amitriptyline, Nortriptyline, Venlafaxine, Duloxetine.

For pre-screening, please contact: Reach out to the disease specific research team.