XL092 and Cemiplimab for the Treatment of BRAF V600E-Wild Type Anaplastic Thyroid Cancer, NEO-COMBAT XL Trial

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
• Subjects is willing and able to comply with study procedures based on the judgement of the investigator
• Age ≥ 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Pathologic findings supporting the clinical impression of ATC * Terminology consistent or suggestive of diagnosis may include the following: anaplastic thyroid carcinoma, undifferentiated carcinoma, squamous carcinoma; carcinoma with spindled, giant cell, or epithelial features; poorly differentiated carcinoma with pleomorphism, extensive necrosis with tumor cells present
• Subject is willing to have a fresh biopsy least 3 days prior to neoadjuvant therapy if archival tissue is unavailable. Also willing to have a biopsy at the time of SOC surgery, if applicable
• Must have BRAF V600E mutation-negative tumor, as determined by BRAF V600E immunohistochemistry on tumor tissue or genetic/molecular testing of tumor
• Patient has either resectable, unresectable disease, or oligometastatic disease at time of enrollment. Patients with oligometastatic disease should be treated prior to initiation of study treatment, based on the treatment team's discretion. Oligometastatic disease is defined as ≤ 5 metastatic lesions occurring at ≤ 3 distinct anatomic locations. Radiation therapy for oligometastatic disease should be completed within 7 days before first dose of study treatment. Repeat imaging post-treatment of oligometastatic disease is not required prior to initiation of study
• Measurable disease on exam or imaging (CT neck with contrast & PET/CT per standard of care) at time of screening and within 28 days of signing consent
• Hemoglobin (Hgb) ≥ 9.0 g/dL (obtained within 28 days prior to initiating study treatment) without transfusion within 2 weeks prior to screening laboratory sample collection * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (≥ 1.5 GI/L) (obtained within 28 days prior to initiating study treatment) without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Platelets ≥ 100 x 10^9/L (obtained within 28 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• International normalized ratio (INR) ≤ 1.5 (obtained within 28 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN) (obtained within 28 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Creatinine ≤ 1.5 x ULN (obtained within 28 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine (obtained within 28 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Bilirubin ≤ 1.5 x ULN (obtained within 28 days prior to initiating study treatment) * Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin < 3.0 mg/dL * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN (obtained within 28 days prior to initiating study treatment) * For subjects with documented bone metastasis ALP ≤ 5 x ULN. For subjects with CRPC and bone metastasis ALP ≤ 10 x ULN if predominantly bone-specific ALP * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Safe, unobstructed airway as documented by a flexible fiberoptic laryngoscopy or presence of a tracheostomy. If there are airway concerns, emergent tracheostomy is acceptable and would affect eligibility
• Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to study treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone [FSH] level > 40 mIU/mL to confirm menopause). Documentation of postmenopausal status must be provided. Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 6 months after last dose of XL092 and cemiplimab. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label. In addition, women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 96 days after the last dose of study therapy
• Recovery to baseline or ≤ grade 1 severity (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of mineralocorticosteroid)

Exclusion Criteria

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). Females should not breastfeed while receiving study treatment and for 1 month from the last dose of XL092
• Patients who have had prior exposure to any immune modulating agents or any type of small molecule kinase inhibitor (including investigational agents) and have documented disease progression on these agents will not be eligible * Radiation therapy for oligometastatic disease should be completed within 7 days before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy must have resolution of symptoms prior to initiation of study treatment
• Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments (i.e., with use of disease modifying agents, corticosteroids (> 10 mg of prednisone or equivalent) or immunosuppressive drugs) which may suggest risk of immune-mediated AEs. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment
• Subject history of documented allergic reactions or acute hypersensitivity reactions attributed to antibody treatments
• Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy within 7 days of initiating treatment
• Participation in another clinical study with an investigational product during the last 3 weeks
• Any concurrent chemotherapy, intraperitoneal (IP), biologic, or hormonal therapy for cancer treatment with the exception of those mentioned in this protocol. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent
• The subject has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to study therapy administration. Subjects requiring systemic corticosteroids at doses higher than the equivalent of prednisone 10 mg QD should hold treatment with cemiplimab until a taper of steroids has been completed. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection) * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Subject has an active systemic infection requiring therapy
• Subject has a history of interstitial lung disease
• Subjects who require or may require pneumonectomy, as assessed by their surgeon, to obtain potentially curative resection of primary tumor
• Have clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study treatment, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication). Subjects are required to have a normal left ventricular ejection fraction as determined by either echocardiography. Subjects must have a Fridericia’s formula–corrected QT interval (QTcF) ≤ 470 msec within 14 days per electrocardiogram (ECG) before first dose of study treatment (Note: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility)
• Known documented brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment * Note: Subjects with an incidental finding of an isolated brain lesion < 1 cm in diameter may be eligible after principal investigator approval if the lesion is radiographically stable for 4 weeks before first dose and does not require treatment per investigator judgement * Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin, and factor Xa inhibitors) and platelet inhibitors (e.g., clopidogrel) * Note: Allowed anticoagulants are low-dose aspirin for cardioprotection (per local applicable guidelines) and low molecular weight heparins (LMWH). Therapeutic doses of LMWH are not permitted in subjects with known brain metastases * Note: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer
• Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
• Lesions invading major blood vessels include, but not limited to, inferior vena cava, pulmonary artery, or aorta. Note: Subjects with intravascular tumor extension (eg, tumor thrombus in renal vein or inferior vena [V.] cava) may be eligible following principal investigator approval
• Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Note: patients with HIV who have undetectable viral loads within the last 3 months are eligible for study participation
• Known positive test for or suspected infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within one month before enrollment. Note: demonstration that the subject has fully recovered from the infection is required to be eligible for enrollment
• Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions
• Subject has malabsorption syndrome
• Pharmacologically uncompensated, symptomatic hypothyroidism
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Requirement for hemodialysis or peritoneal dialysis
• History of solid organ or allogeneic stem cell transplant
• Surgery exclusion criteria: * Major surgery (e.g., gastrointestinal [GI] surgery, laparoscopic procedures, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of therapy ** Complete wound healing from major surgical procedure must have occurred within 28 days prior to the first dose of therapy * Minor procedures (e.g., simple excision, tooth extraction) within 10 days before first dose of study treatment ** Complete wound healing from minor surgery must have occurred at least prior to the first dose of study treatment ** Note: Baseline biopsies are permitted and should be performed at least 3 days before the first dose of study treatment
• Subject has an inability to swallow tablets or ingest a dispersion either orally or by a nasogastric (NG) or gastrostomy (PEG) tube
• Previously identified allergy or hypersensitivity to components of the study treatment formulations
• Any other active malignancy or diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6
• Known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease
• Subject history of pneumonitis within the last 5 years. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Free thyroxine (FT4) outside the laboratory normal reference range. FT4 abnormalities deemed clinically insignificant by the principal investigator can be deemed eligible
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment and until 6 months after last dose of therapy