IRB Study Number 23-1004
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
• To determine the preliminary RP2D of single-agent petosemtamab in mCRC patients who have progressed on chemotherapy, with or without an anti-VEGF therapy, and with an anti-EGFR therapy (if RASwt)
Secondary Objectives
• To characterize the safety and tolerability of petosemtamab
• To evaluate preliminary antitumor activity
• To characterize the PK of petosemtamab
• To characterize the immunogenicity of petosemtamab
• To correlate biomarkers in tumor samples relevant to EGFR and LGR5 as well as the early tumor response profile of petosemtamab
Inclusion Criteria
Signed informed consent form (ICF) before initiation of any study procedures
Age ≥18 years at signing of ICF
Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent:
• Expansion cohorts: patients with locally advanced unresectable or metastatic disease for the following indications:
COMBINATION
o FIRST-LINE HNSCC: patients eligible to receive pembrolizumab as first-line monotherapy with tumors expressing PD-L1, CPS ≥1, as determined by an FDA-approved test in the US, or by an approved equivalent test in other countries; patients should not have previous systemic therapy administered in the recurrent or metastatic setting, although previous systemic therapy as part of multimodal treatment for locally advance disease is allowed if ended ≥6 months prior to signing the ICF. The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Previous treatments with anti-PD-(L)1 or anti-EGFR therapies are not allowed.
SINGLE AGENT
o SECOND-/THIRD-LINE HNSCC PATIENTS: patients who have progressed on or after, or are intolerant to, anti-PD-(L)1 therapy as monotherapy or in combination with other agents, and have progressed to a platinum-based chemotherapy less than 6 months from the last platinum dose, with no previous exposure to EGFR inhibitors. Patients with no more than 2 prior lines of treatment in recurrent or metastatic disease not amenable to standard therapy with curative intent.
Human papilloma virus (HPV) status determined by p16 immunohistochemistry (IHC) or molecular HPV test for all oropharyngeal tumors should be reported when available.
The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
o Cancers of the anogenital tract with squamous cell histology (cervical, vaginal, vulvar, penile, anal)
o NSCLC SCC
o NSCLC non-SCC
o GEA with histologically confirmed EGFR amplification (fluorescence in situ hybridization [FISH] score EGFR/CEP7 ratio ≥2.0, or next generation sequencing [NGS] EGFR copy ≥8, or cfDNA ≥2.5, or EGFR IHC H-score ≥200)
o Esophageal carcinoma
o Pancreatic adenocarcinoma
o CRC with no confirmed mutations in RAS, BRAF or other oncogenic drivers associated with resistance to antibody-based EGFR inhibition, by cfDNA, or next generation sequencing [NGS] on tumor tissue
Other indications may be considered, such as malignant salivary gland tumors.
• Note 1: Patients with NSCLC must receive all recommended standard therapies driven by the histological subtype and tumor molecular profile.
• Note 2: Patients with CRC must be previously treated in the metastatic setting with standard approved therapy including oxaliplatin, irinotecan and fluoropyrimidines (5-FU and/or capecitabine) + an anti-EGFR ± an anti-angiogenic agent, with complete or partial response to the anti-EGFR antibodies. Prior treatment with either regorafenib or trifluridine/tipiracil is allowed. CRC patients with previous exposure to EGFR inhibitors must have ≥6 months since progression on the EGFR inhibitor.
• Note 3: Patients with other indications must have been previously treated with at least 2 lines of the standard approved therapy (when applicable) in the locally advanced/unresectable or metastatic setting. Patients with malignant salivary gland tumors and squamous esophageal cancer may be enrolled after progression on 1 line of systemic standard treatment.
A baseline new tumor sample (formalin-fixed paraffin-embedded [FFPE]) from a metastatic or primary site. If the patient has an available tumor sample as an FFPE block with sufficient material (at least 20 slides with >20% tumor content) and has not received further anticancer treatment since sample collection, a new tumor biopsy at baseline is not necessary. Archival FFPE slides are not acceptable. In the case of HNSCC, GEA, and SC-NSCLC, primary tumor material is only acceptable if the patient has not been treated with anti-EGFR or anti-human epidermal growth factor receptor (HER)-2 therapies.
Amenable for biopsy
Measurable disease as defined by RECIST version 1.1 by radiologic methods
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Life expectancy ≥12 weeks, as per investigator
Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or multigated acquisition scan (MUGA)
Adequate organ function:
• ANC ≥1.5 X 109/L
• Hemoglobin ≥9 g/dL
• Platelets ≥100 x 109/L
• Corrected total serum calcium within normal ranges
• Serum magnesium within normal ranges (or corrected with supplements)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN (unless due to known Gilbert’s syndrome who are excluded if total bilirubin >3.0 x ULN or direct bilirubin >1.5 x ULN); in cases of liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed, unless due to known Gilbert’s syndrome when total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN will be allowed or hepatocellular carcinoma [Child-Pugh class A] when total bilirubin <3 mg/dL will be allowed.
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥60 mL/min calculated according to the Cockroft and Gault formula or Modification of Diet in Renal Disease (MDRD) formula for patients aged >65 years (Section 19.2, Appendix 2)
• Serum albumin ≥3 g/dL
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5 x ULN unless patient is receiving anticoagulant therapy and in therapeutic range of intended used anticoagulant
• Activated partial thromboplastin time (APTT) or PTT ≤1.5 x ULN unless patient is receiving anticoagulant therapy and is in therapeutic range of intended used anticoagulant
- Willing to undergo testing for human immunodeficiency virus (HIV) if not tested within the past 6 months. HIV-positive patients are eligible provided the CD4+ count is ≥300/μL, viral load is undetectable, and the patient is currently receiving highly active antiretroviral therapy (HAART).
Exclusion Criteria
Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 14 days of study entry
Known leptomeningeal involvement
Participation in another clinical trial or treatment with any investigational drug within 4 weeks prior to study entry
Any systemic anticancer therapy within 4 weeks or 5 half-lives, whichever is longer, of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity (eg, mitomycin C, nitrosoureas), or anticancer immunotherapies, a washout period of 6 weeks is required.
Requirement for immunosuppressive medication (eg, methotrexate, cyclophosphamide)
Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible, irrespective of when it was received.
Persistent Grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤Grade 2 National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 is allowed.
History of hypersensitivity reaction or any toxicity attributed to human proteins or any of the excipients that warranted permanent cessation of these agents
Uncontrolled hypertension (systolic BP >150 mmHg and/or diastolic BP >100 mmHg) with appropriate treatment, or unstable angina
History of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia)
History of myocardial infarction within 6 months of study entry
History of prior malignancies with the exception of excised cervical intraepithelial neoplasia or nonmelanoma skin cancer, or curatively treated cancer deemed at low risk for recurrence with no evidence of disease for at least 3 years
Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy
Patients with a history of interstitial lung disease (ILD) (eg, pneumonitis or pulmonary fibrosis), or evidence of ILD on baseline chest computerized tomography (CT) scan
Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders
Patients with the following infectious diseases:
• Active hepatitis B surface antigen infection (HBsAg positive) without receiving antiviral treatment. Note:
o Patients with active hepatitis B (HBsAg positive) must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least ≥7 days before the initiation of study treatment.
o Patients with antecedents of hepatitis B (anti-HBc positive, HBsAg and hepatitis B virus [HBV]-DNA negative) are eligible.
• Positive test for hepatitis C virus (HCV) ribonucleic acid (RNA). Note: Patients in whom HCV infection resolved spontaneously (ie, positive HCV antibodies without detectable HCV-RNA) or who achieved a sustained response after antiviral treatment and show absence of detectable HCV RNA ≥6 months (with the use of IFN-free regimens) or ≥12 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible.
Patients with current cirrhotic status of Child-Pugh class B or C; known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
Pregnant or breastfeeding patients; patients of childbearing potential must use highly effective contraception methods prior to study entry, for the duration of study participation, and for 6 months after the last dose of petosemtamab.
HNSCC first-line combination cohort: has a diagnosis of immunodeficiency, or is receiving systemic steroid therapy or any form of immunosuppressive therapy within 7 days prior to the first dose. Corticosteroids use as premedication for allergic reactions or IRRs specified in the protocol are allowed.
HNSCC first-line combination cohort: active autoimmune disease that has required systemic immune suppressive treatment in the past 2 years; replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered immune suppressive treatment.
HNSCC first-line combination cohort: has had an allogeneic tissue/solid organ transplant
HNSCC first-line combination or HNSCC single-agent cohort: patients may not have a primary tumor site of nasopharynx (any histology).
GEA cohort: patients previously treated with anti-EGFR inhibitors are not eligible for this study.
