Head and Neck Cancer

Key Eligibility:
1. Recurrent oral cavity, larynx, oropharynx, hypopharynx in previously radiated field (>6 mo ago)
2. s/p salvage resection with high-risk disease: +margins and/or +ENE
3. Visits: daily RT; weekly visits during RT; every 6 weeks for ~11 mo; q6m phone calls for 5 years

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

1. Have histologically or cytologically confirmed R/M HNSCC that is considered
incurable by local therapies.
2. The eligible primary tumor locations are the oral cavity, oropharynx, hypopharynx, or larynx.
3. Must not have a primary tumor site of nasopharynx (any histology) or primary tumor of unknown location.
4. Must have documented local testing results per local regulations using a 22C3 antibody assay for PD-L1 status to determine the CPS within 6 months prior to
C1D1.
5. HPV status must be known for participants with primary tumor location in oropharynx via p16 test, HPV DNA test, or high-risk HPV ISH. Any known p16, HPV DNA, or high-risk HPV ISH status of tumor must be negative.
6. ECOG performance status of 0 or 1.
7. Be treatment-naïve for systemic therapy in the R/M setting. Systemic therapy which was completed more than 6 months prior to signing consent, if given as part of treatment for locally advanced disease with curative intent, is allowed. The participant must not have had disease progression within 6 months of completion of curative systemic therapy for locally advanced disease.

Patient Eligibility Criteria:
1. Histologically or cytologically confirmed R or M HNSCC. Eligible primary tumor locations are oral cavity, hypopharynx, larynx or oropharynx (with documented HPV-negative disease if presenting with OPSCC).
Note: Primary tumor location of paranasal sinuses and nasopharynx, any histology are excluded.
2. No prior systemic therapy administered in the R or M setting; and completed systemic therapy >6 months prior if given as part of multimodal treatment for locoregionally advanced disease in the adjuvant or definitive setting.
3. Documentation of HPV-negative disease per central testing if presenting with OPSCC. Tumor tissue from excisional/incisional or core biopsy (fine needle aspirates and bone biopsies are not acceptable) must be provided for central testing. Archival tumor tissue is acceptable. A fresh tumor biopsy, using a procedure that is safe for the subject on a lesion not previously irradiated (unless lesion progressed) will be required if tumor tissue is not available.
Note: To be eligible to participate in this study, subjects with OPSCC must have HPV-negative documentation based on testing performed by a central laboratory.
4. Documented tumor PD-L1 CPS >/=1 (by PD-L1 IHC 22C3 pharmDx assay), determined locally or centrally. If local documentation of PD-L1 is not available, tumor tissue from excisional or core biopsy (fine needle aspirates and bone biopsies are not acceptable) must be provided for central testing to determine eligibility (see further details regarding archival tissue collection Section 7.10).
5. Measurable disease based on RECIST 1.1 as determined by BICR. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated. Baseline Scan must be transferred to BICR for assessment.
6. ECOG performance status of 0 or 1.

Key Eligibility Criteria:
Inclusion Criteria:
1. Have histologically or cytologically confirmed cancer diagnosis based on pathology report.
2. Willing to submit a pre-treatment (archival or fresh-tissue if no archival tissue is available) and on-treatment tissue sample. Additionally, during the dose-escalation portion and if appropriate in the expansion phase of the study, the Sponsor may modify subject enrolment into various cohorts that have not begun enrolling yet such that ENPP1 and/or cGAS baseline expression level in the subject's tumor must be available and may guide enrolment eligibility for the study.

Exclusion Criteria:
1. Subjects with evidence of rapid progression on prior therapy resulting in rapid clinical deterioration should be excluded from participation in the trial.
2. Uncontrolled tumor-related pain
3. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
4. History or any evidence of interstitial lung disease

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