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
Willing and able to provide signed ICF prior to initiation of any study procedures. Patients unable to provide their own consent will not be eligible to participate in the study.
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, and disease progression on the last line of therapy (when applicable):
• Expansion cohorts: patients with locally advanced unresectable or metastatic disease for the following indications:
SINGLE AGENT
o 2L/3L HNSCC: patients who have progressed on or after, or are intolerant to, anti-PD-(L)1 and platinum therapy as monotherapy or in combination with other agents and no previous exposure to EGFR inhibitors. Patients treated with platinum-containing therapy only in the adjuvant setting, or in the context of multimodal therapy for locally advanced disease, should have disease progression within 6 months of the last dose of platinum containing therapy. Patients should not have received more than 2 prior lines of treatment in recurrent or metastatic disease.
▪ Human papillomavirus (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 3L+ mCRC; patients must have:
▪ No oncogenic missense mutations in KRAS, NRAS, BRAF, or EGFR ectodomain (as defined in Section 7.1.3), and no HER2 (ERBB2) amplification, as detected in plasma by ctDNA NGS central testing performed during screening.
▪ A microsatellite stable (MSS) tumor.
▪ Received ≥2 and no more than 4 lines of prior therapy in the metastatic setting including 1) chemotherapy with oxaliplatin, irinotecan, and a fluoropyrimidine, and 2) targeted therapy with an anti-VEGF and an anti-EGFR inhibitor. Petosemtamab treatment would be considered first-line in the advanced setting if disease progression had occurred within 6 months of completion of adjuvant or neoadjuvant therapy.
▪ 1) a documented best response of CR, PR, or any tumor reduction on a prior EGFR inhibitor received in any line as monotherapy or in combination with chemotherapy; 2) ≥6 months of treatment with an EGFR inhibitor without progression; and 3) an interval of ≥6 months since the last administration of EGFR inhibitor at the time of study treatment.
o Esophageal SCC: patients with advanced recurrent or metastatic disease who have progressed on or are intolerant to previous chemotherapy and anti-PD-(L)1 treatment (concomitant or sequential). Patients may have received chemoradiotherapy in the neoadjuvant, recurrent, or metastatic setting. Patients must not have received more than 1 prior line of chemotherapy in the metastatic setting.
COMBINATION
o 1L HNSCC: patients eligible to receive pembrolizumab as 1L 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 advanced disease is allowed if it 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.
o mCRC: patients previously diagnosed with histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the colon or rectum. Patients must have documented KRAS/NRAS/BRAF WT status as determined using tumor tissue (primary or metastatic) by an appropriate tumor tissue-based assay to be confirmed by the Sponsor, and must have an MSS tumor. Patients must be naive to prior anti-EGFR therapy.
▪ mCRC treated with petosemtamab and FOLFIRI: patients may have received up to 1 prior chemotherapy regimen in the metastatic setting consisting of 1L fluoropyrimidine-oxaliplatin-based chemotherapy ± bevacizumab. Note 1: FOLFOX-based adjuvant treatment would be considered first-line if disease progression occurred within 6 months of completion of adjuvant therapy. Note 2: If the initial treatment included maintenance therapy, the induction regimen with FOLFOX or any other oxaliplatin-based regimen must have lasted ≥4 months. Note 3: Prior FOLFIRINOX is not permitted.
▪ mCRC treated with petosemtamab and FOLFOX: patients may have received up to 1 prior chemotherapy regimen in the metastatic setting consisting of 1L fluoropyrimidine-irinotecan-based chemotherapy ± bevacizumab. Note 1: If the initial treatment included maintenance therapy, the induction regimen with FOLFIRI or any other irinotecan-based regimen must have lasted ≥4 months. Note 2: Prior FOLFIRINOX is not permitted.
Able to provide a formalin-fixed paraffin-embedded (FFPE) block with sufficient tumor material or a minimum of 20 freshly cut unstained slides of tumor tissue (FFPE blocks are preferred). For patients who have progressed on prior treatments, it is preferred that biopsies were collected after completion of such therapies (eg, after anti-EGFR therapy for 3L+ mCRC). If archival tumor tissue is not available, a tumor biopsy may be performed prior to the start of treatment.
Amenable for biopsy (if safe/feasible).
Measurable disease as defined by RECIST v1.1 by radiologic methods.
ECOG PS of 0 or 1.
Life expectancy ≥12 weeks, as per investigator.
Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
Adequate organ function:
• ANC ≥1.5 x 109/L; mCRC FOLFOX combination: ANC >2 x 109/L.
• Hemoglobin ≥9 g/dL.
• Platelets ≥100 x 109/L.
• Serum magnesium, sodium, corrected total calcium, phosphate, and potassium within normal ranges (or corrected with supplements or appropriate treatment).
• 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 ≤1.5 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.
• Serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl) ≥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 (Appendix 2, Section 20.2).
• 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 partial thromboplastin time (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. Known HIV-positive patients are eligible provided the cluster of differentiation 4 (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 study 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 shorter, 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 to any of the excipients of petosemtamab, human proteins, or any combination treatment required for this study.
Uncontrolled hypertension (systolic BP >150 mmHg and/or diastolic BP >100 mmHg) with appropriate treatment; 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); or 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 ≥3 years.
Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy, including patients with a history of 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 known infectious diseases:
• Active hepatitis B infection (hepatitis B surface antigen [HbsAg] positive) without receiving antiviral treatment. Note:
o Patients who are 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 (eg, anti-hepatitis B core (anti-HBc) positive, HbsAg, and hepatitis B virus [HBV]-DNA negative) are eligible.
• Positive test for hepatitis C virus (HCV) 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 interferon [IFN]-free regimens) or ≥12 months (with the use of IFN-based regimens) after cessation of antiviral treatment, are eligible.
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 (see Section 9.12 for combination therapy requirements).
1L HNSCC 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 used as premedication for allergic reactions or IRRs specified in the protocol are allowed.
1L HNSCC 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.
1L HNSCC combination cohort: has had an allogeneic tissue/solid organ transplant.
1L HNSCC combination or HNSCC single-agent cohort: patients may not have a primary tumor site of nasopharynx (any histology).
Previously treated with EGFR inhibitors (except 3L+ mCRC, see inclusion criterion #3).
mCRC combination cohorts: a documented oncogenic RAS/RAF mutation in disease history.
mCRC combination cohorts: patients with an active inflammatory bowel disease, or other bowel disease causing chronic diarrhea (defined as NCI-CTCAE Grade ≥2).
mCRC combination cohorts: patients with peripheral sensory neuropathy with functional impairment (defined as NCI-CTCAE Grade ≥3).
mCRC combination cohorts: patients must not have received any live vaccines within 4 weeks prior to the first dose.
3L+ mCRC cohort: a documented oncogenic KRAS, NRAS, BRAF, or EGFR ectodomain mutation, or HER2 amplification identified by tumor test or ctDNA test in disease history, or during central ctDNA screening.
Esophageal SCC: patients with evidence of fistula (esophageal/bronchial or esophageal/aorta, or other) or of complete esophageal obstruction not amenable to treatment.
