IRB Study Number 22-666
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To characterize the safety, tolerability, and maximum tolerated dose/recommended dose for expansion of BCA101 alone and BCA101 in combination with pembrolizumab or encorafenib
Secondary Objectives
To explore the preliminary anti-tumor activity of BCA101 alone and BCA101 in combination with pembrolizumab or encorafenib
To characterize the PK profile of BCA101 alone and in combination with pembrolizumab or encorafenib
To evaluate the immunogenicity of BCA101 alone and in combination with pembrolizumab or encorafenib
Exploratory Objective
To explore pharmacodynamic markers and biomarkers for BCA101
Inclusion Criteria
Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the study prior to enrollment.
Patient is ≥18 years of age on the day of signing informed consent.
Patient must have measurable disease amenable to biopsy and be willing to undergo both a pre-treatment and on-treatment biopsy, as well as provide archival tumor if available from the primary tumor (a paraffin embedded tumor tissue block sufficient to obtain at least 20 sections of 4 to 10 micrometer thickness). If a patient has a tumor type that is not amendable to biopsy, the biopsy may be waived after discussion and approval from the Sponsor
Life expectancy ≥12 weeks as assessed by the Investigator
Tumor eligibility:
PART A (Dose Escalation):
a. Patient must have histologically or cytologically confirmed, EGFR-driven, advanced solid tumors refractory to current standard of care therapy:
i. Single agent BCA101 – patients with the following tumor types will be eligible:
1) SQCLC
2) HNSCC
3) CRC RAS WT MSS
4) TNBC
5) Chordoma
6) SCAC
7) Uveal melanoma
8) GBM
9) Gastric cancer
10) Any solid tumor with a KRAS G12D or G13D mutation
11)Any solid tumor with EGFR amplification
12) Epithelial ovarian cancer
13)Hepatocellular carcinoma (HCC)
14)Anaplastic thyroid cancer (ATC)
15) Pancreatic cancer
16)Other EGFR-driven advanced solid tumors (if there is compelling data or evidence to enroll a patient with a tumor type other than those listed in 1 – 15, the treating physician may discuss the patient with the Sponsor to determine eligibility).
ii. Combination BCA101 and pembrolizumab – patients with the following tumor types will be eligible:
1) HNSCC
2) SCAC
Dose De-escalation
i. Combination BCA101 and encorafenib – patients with the following tumor types will be eligible:
• BRAF V600E mutant-positive metastatic Colorectal Cancer (mCRC)
PART B (Cohort expansion):
b. Patients must have histologically or cytologically confirmed, advanced solid tumors:
i. Single agent BCA101 – patients with the following tumor type will be eligible:
• Expansion Cohort 1: Cutaneous Squamous Cell Carcinoma (CSCC) –
i. patients must have received (or been intolerant to or ineligible for) prior anti-PD-1 therapy in the metastatic or locally advanced setting.
ii. No prior history of treatment with anti-EGFR antibodies in the unresectable/metastatic setting (prior treatment with radiotherapy in the adjuvant setting is allowed).
ii. Combination BCA101 and pembrolizumab – patients with the following tumor types will be eligible:
• Expansion Cohort 2: Head and Neck Squamous Cell Carcinoma (HNSCC), metastatic or unresectable, recurrent with a Combined Positive Score (CPS) equal to or greater than 1, as determined by an CLIA-approved laboratory test. Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology).
i. 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).
ii. 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.
iii. Patients must have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer
Note: To remain representative of the general population, approximately 30% of all HNSCC patients enrolled in this expansion cohort should be HPV positive and approximately 70% of the patients enrolled should be HPV negative.For subjects with oropharyngeal cancer, must have results from testing of HPV status, defined as p16 expression by IHC analysis. Subjects with hypopharynx, larynx and oral cavity cancer are not required to undergo HPV testing by p16 IHC.
• Expansion Cohort 3: Squamous Carcinoma of the Anal Canal (SCAC), locally advanced/unresectable or metastatic.
i. Patients must have received (or been intolerant to or ineligible for) at least 1 prior line of chemotherapy and received no more than 2 prior lines of systemic treatments for treatment of unresectable and/or metastatic disease. No prior history of immune checkpoint inhibitors (exception of neoadjuvant).
iii. Combination BCA101 and encorafenib – patients with the following tumor type will be eligble:
• Expansion Cohort 4: BRAF V600E mutant-positive metastatic Colorectal Cancer (mCRC).
i. Presence of BRAF V600E mutation and absence of a RAS mutation in tumor tissue as previously determined by an CLIA-approved laboratory test at any time prior to screening. Patients must have progression of disease after 1 or 2 prior therapy in the metastatic setting.
ii. No prior treatment with RAF inhibitors. No prior history of anti-EGFR antibodies.
Patient must have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
Patient must have measurable disease (computed tomography [CT]/magnetic resonance imaging [MRI] scans performed within 21 days before C1D1 visit are acceptable), i.e., at least 1 unidimensional measurable lesion as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) and Immune Response Evaluation Criteria in Solid Tumors (iRECIST).
Prior therapies:
a. In Part A (dose escalation), patients must be refractory to, have failed, or be intolerant to or ineligible for standard therapy for their malignancy or have a tumor type where no approved therapy exists. Patients may have received prior treatment with checkpoint inhibitors including pembrolizumab (either as approved or investigational therapy) and may have received prior treatment with cetuximab or other anti-EGFR therapies.
b. In Part B (dose expansion) depending on the indication, patients will either be treatment naïve or refractory, have failed or be intolerant to first line therapy as stated in Inclusion Criteria 5.
- Adequate organ function as defined by the following criteria:
a. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities exist in the presence of liver metastasis.
b. Total serum bilirubin ≤1.5 x ULN (except for patients with documented Gilbert’s syndrome).
c. Absolute neutrophil count ≥1500/μL.
d. Platelets ≥100,000/μL.
e. Hemoglobin ≥9.0 g/dL or 5.6 mmol/L. Must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin (≥ approximately 3 months).
f. Serum creatinine ≤1.5 x ULN OR creatinine clearance (CrCl) measured or calculated per institutional standard (GFR can also be used in place of creatinine or CrCl).
Resolution of all acute toxic effects of prior therapy or surgical procedures to ≤ Grade 1 (patients with neuropathy of Grade 2 or less, and patients with any grade of alopecia are allowed).
Patients must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
For encorafenib arm only: Patient much be able to swallow capsules.
Exclusion Criteria
For Part A: Exposure to anti-EGFR antibodies within 4 weeks of the first dose of study drug.
Prior treatment with any anti-TGFβ therapy.
Prior history of Grade ≥ 2 intolerance or hypersensitivity reaction to cetuximab or other anti-EGFR therapy or other murine proteins or prior discontinuation of therapy in the setting of toxicity related to treatment.
Major surgery (including eye surgery), radiation therapy (localized radiation therapy for palliative intent within 4 weeks is allowed if agreed upon after discussion between the Sponsor and treating physician), or systemic anticancer therapy within 4 weeks of the first dose of study drug (4 weeks or 5 half-lives, whichever is shorter, for chemotherapy, targeted therapies and biologics).
An expectation that the patient will require any other form of antineoplastic/biological therapy during the study.
Known history of a hematologic malignancy (or solid tumor other than the ones indicated for this study), unless the patient has undergone potentially curative therapy with no evidence of that disease for 2 years. Does not include tumors with a negligible risk of metastasis or death (e.g. adequately treated basal or squamous cell carcinoma of the skin, stage 1 prostate cancer, or carcinoma in situ of the cervix or carcinoma in situ of the breast). Subjects enrolling in the CSCC cohort may have chronic lymphocytic leukemia as long as the patient is not on active treatment.
For non-GBM patients only: Patients with active central nervous system (CNS) metastases, a history of spinal cord compression from tumor involvement, a history of carcinomatous meningitis or leptomeningeal disease are excluded. Patients with a history of treated CNS metastases (by surgery or radiation therapy) may be eligible if CNS metastases have been stable for at least 2 months, i.e., without evidence of progression by repeat imaging, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
Any of the following within 6 months before starting study drug: Myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident, including transient ischemic attack or pulmonary embolus. Patients with a history of clinically significant cardiac valvular disease will not be eligible. Patients with deep vein thrombosis that are hemodynamically stable are alloed to enroll as long as they are on a stable dose of anticoagulants for at least 3 months. Patients with thromboembolic evens related to port-a-caths are not excluded.
Current active or uncontrolled bleeding or a history of an active gastrointestinal bleeding episode within 4 weeks prior to enrollment.
Receipt of systemic thrombolytic agent within 28 days before enrolment. Any known coagulopathies. Patients on a stable dose of oral anticoagulants or low molecular weight heparin for at least 28 days prior to enrollment are eligible.
A history of retinal disease or known evidence of retinal pathology that may suggest a risk factor for retinal detachment or retinal/vitreous hemorrhage.
Pregnant or breastfeeding women.
Any condition requiring systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 14 days prior to the first dose of study drug, with the exception of topical, intranasal, intrabronchial, or ocular steroids.
Use of a live or live-attenuated vaccine within 4 weeks prior to screening.
Note: Administration of killed vaccines are allowed.
Receipt of growth factors within 21 days before the first dose of study drug.
Known or suspected severe hypersensitivity (≥Grade 3) to medications containing anti-EGFR antibodies or any mAb and/or any of its excipients.
Receipt of any organ transplantation, including autologous and allogeneic stem-cell transplantation, with the exception of transplants that do not require immunosuppression (e.g. corneal transplant, hair transplant).
Patients with active or chronic corneal disorders requiring ongoing treatment.
Other severe, acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the Investigator and/or Sponsor, excess risk associated with study participation or study drug administration, and would, therefore, make it inappropriate for the patient to enter this study.
Serious (as judged by the Investigator) systemic infection (bacterial, viral, or fungal) within 4 weeks before the first dose of study drug, or active systemic infection requiring either hospitalization or parenteral anti-infective therapy within 2 weeks before the first dose of study drug.
Clinically significant history of alcohol or drug abuse.
Known cases of human immunodeficiency virus (HIV) are excluded if patients have a CD4+ T-cell (CD4+) count <350 cells/mm3. To ensure that effective antiretroviral therapy (ART) is tolerated and that toxicities are not confused with investigational drug toxicities, trial participants must be on established ART, without changes in drugs or dose modification, for at least four weeks prior to C1D1 and have an HIV viral load less than 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.
HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are also excluded.
- Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy and are not on a suppressive antiviral therapy prior to initiation of study treatment. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
- Patients with a known history of hepatitis C who have not completed curative antiviral treatment or have a HCV viral load above the limit of quantification at screening.
Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
- Participation in another clinical study or treatment with another investigational drug within 4 weeks prior to C1D1 or within a period of 5 half-lives of that agent, whichever is longer.
26.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 8 weeks after stopping medication with BCA101 single agent or BCA101 in combination with encorafenib or for 120 days after stopping medication with BCA101 in combination with pembrolizumab. Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
c. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
d. For BCA101 single agent and BCA101 in combination with pembrolizumab only: Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
Note: For subjects treated with encorafenib, only non-hormonal contraception is acceptable.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 8 weeks after stopping study treatment with BCA101 single agent or for 120 days after stopping medication with BCA101 in combination with pembrolizumab. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
Additional Exclusion Criteria for Part B Expansion Cohort 2 (HNSCC) and Cohort 3 (SCAC):
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher irAE.
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Has a history of (non-infectious) pneumonitis, radiation pneumonitis or interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
Additional Exclusion Criterion for Part B Expansion Cohort 4 (BRAF V600E mutant-positive mCRC):
- Patients with QTcF ≥500 ms at screening.
No additional exclusions may be applied by the Investigator, in order to ensure that the study population will be representative of all eligible subjects.
