Study of Osimertinib with Carotuximab in Advanced, EGFR-mutated Non-Small Cell Lung Cancer

Inclusion Criteria:

• Stage IV or recurrent/metastatic non-squamous NSCLC that harbors an EGFR activatingmutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q, etc). Localtesting for EGFR mutations is acceptable provided it was performed in a CLIAcertified lab.

• Part I: Progressive disease on at least one prior EGFR TKI

• Part II, Cohort 1: Progressive disease on osimertinib or other prior EGFR TKIs

• Part II, Cohort 2: Receiving osimertinib as front line treatment for less than 12weeks. Persistent ctDNA with EGFR mutation between weeks 6-12 from the start ofosimertinib treatment.

• Age at least 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2

• Archival tissue from a biopsy performed after progression of disease on previousEGFR TKI or willing to consent for a fresh tumor biopsy.

• Measurable disease by RECIST 1.1.

• Patients with untreated brain metastases are allowed provided that the patient isclinically asymptomatic and stable.

• Patients must have completed prior chemotherapy ≥ 3 weeks or radiotherapy ≥ 2 weeksprior to receiving study drugs.

• If the subject's most recent line of therapy is treatment with osimertinib, then alladverse events must be resolved to Grade 2 or better

• If the subject's most recent line of therapy is any other treatment thanosimertinib, then all Adverse Events must be resolved to grade 1 or better, with theexception of fatigue, alopecia and neuropathy (which must resolve to CTCAE grade 2).

• Adequate organ function

• Women of childbearing potential and men must agree to use adequate contraceptionwhile on study.

• Written informed consent obtained from subject and ability for subject to complywith the requirements of the study.

Exclusion Criteria:

• Past medical history of interstitial lung disease, drug-induced interstitial lungdisease, radiation pneumonitis requiring steroid treatment, or any evidence ofclinically active interstitial lung disease.

• Small cell lung cancer histology.

• Other prior malignancy that might interfere with study endpoints per opinion of theinvestigator.

• Prior exposure to carotuximab or any CD105 targeted antibody.

• Any major surgical procedure within 2 weeks of starting therapy.

• Patients must not have a history of uncontrolled or poorly-controlled hypertensiondefined as SBP > 150 mmHg or DBP > 90 mmHg within 28 days prior to enrollment.

• Active bleeding or pathologic conditions that carries a high bleeding risk (e.g.gastric ulcers).

• Use of thrombolytics within 10 days prior to the first day of carotuximab.

• Known hypersensitivity to Chinese hamster ovary products or other recombinant human,chimeric, or humanized antibodies.

• A known diagnosis of Osler-Weber-Rendu syndrome.

• Ascites or pericardial or pleural effusion requiring external drainage procedures.

• New evidence of leptomeningeal disease.

• Acute cardiovascular event within the past 6 months.

• Pregnancy or breastfeeding.