Zanzalintinib in Combination with Paclitaxel for the Treatment of Recurrent High Grade Uterine Cancer
This phase I/Ib trial studies the side effects and best dose of zanzalintinib in combination with paclitaxel in treating patients with high grade uterine cancer that has come back after a period of improvement (recurrent). Zanzalintinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Giving zanzalintinib in combination with paclitaxel may be safe in treating patients with recurrent high grade uterine cancer.
Inclusion Criteria
- Diagnosis of recurrent, Federation of Gynecology and Obstetrics (FIGO) grade 3 endometrioid, serous, or mixed high grade uterine or endometrial cancer or uterine carcinosarcoma. Patients must have experienced either prior progression on a platinum-based therapy or intolerance to platinum. Patients with mismatch repair protein deficiency (dMMR) or high-frequency microsatellite instability (MSI-H) tumors or targetable HER2 alterations are required to have received prior therapy with appropriate targeted agents.
- 1-2 prior lines of anti-cancer therapy are allowed.
- Subjects who have received prior treatment with trastuzumab, pembrolizumab, or dostarlimab can enroll in the study. Use of these agents together or as maintenance therapy is considered 1 regimen.
- Recovery to baseline or ≤ grade 1 severity (Common Terminology Criteria for Adverse Events version 5 [CTCAE v5]) 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 corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, ≤ grade 2 neuropathy are permitted).
- Patients must have disease that cannot be managed by local therapy targeted at the tumor site (i.e. surgery, radiation therapy).
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- At least 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
- Absolute neutrophil count ≥ 1.5 K/cumm (within 14 days prior to first dose of study treatment) without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection.
- Platelets ≥ 100 K/cumm (within 14 days prior to first dose of study treatment) without transfusion within 2 weeks of screening laboratory sample collection.
- Hemoglobin ≥ 9.0 g/dL (within 14 days prior to first dose of study treatment) without transfusion within 2 weeks prior to screening laboratory sample collection.
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (for subjects with Gilbert’s disease ≤ 3 x upper limit of normal [ULN]) (within 14 days prior to first dose of study treatment).
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN (within 14 days prior to first dose of study treatment). For subjects with documented bone metastasis ALP ≤ 5 x ULN.
- Serum creatinine < 1.5 x ULN OR calculated or measured creatinine clearance ≥ 40 mL/min (using Cockcroft-Gault equation) (within 14 days prior to first dose of study treatment).
- International normalized ratio (INR) ≤ 1.5 x IULN (within 14 days prior to first dose of study treatment).
- Activated partial thromboplastin time (aPTT) ≤ 1.2 x IULN (within 14 days prior to first dose of study treatment).
- Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine (within 14 days prior to first dose of study treatment).
- Female subjects of child-bearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (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). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. Should a patient become pregnant or suspect pregnancy while participating in this study, the treating physician must be informed immediately.
- The effects of zanzalintinib on the developing human fetus are unknown. For this reason and because chemotherapeutic agents are known to be teratogenic, patients of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and through 186 days after last dose of zanzalintinib or paclitaxel for women of child-bearing potential (WOCBP). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
- Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria
- Any prior treatment with zanzalintinib.
- A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease.
- Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment, or any prior treatment with any tyrosine kinase inhibitor (TKI).
- Receipt of any other (non-study) cytotoxic chemotherapy, radiation, targeted treatment, or immunotherapy (including investigational) within 4 weeks prior of start of study treatment.
- Receipt of any other investigational agents or has received an investigational agent within 4 weeks of start of study treatment.
- Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
- Known 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: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed.
- Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin inhibitors) and platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: * Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). * Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. * 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.
- The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Unstable or deteriorating cardiovascular disorders: ** Congestive heart failure New York Heart Association class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes). ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. ** Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment. ** Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment. *** Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. *** Note: Subjects who don’t require prior anticoagulation therapy may be eligible but must be discussed and approved by the principal investigator. ** Prior history of myocarditis. * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** Tumors invading the GI-tract from external viscera ** Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis ** Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before first dose unless cause of obstruction is definitively managed and subject is asymptomatic ** Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. *** Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment. ** Known gastric or esophageal varices ** Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks ** If tolerating PO, small bowel obstruction can be included.
- 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.
- Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed).
- Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta.
- Other clinically significant disorders that would preclude safe study participation. * Active infection requiring systemic treatment. Note: Prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are allowed. * Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness except for subjects meeting all of the following criteria: (1) on stable anti-retroviral therapy; (2) CD4+ T cell count ≥ 200/µL; and (3) an undetectable viral load. Note: HIV testing will be performed at screening if and as required by local regulation. Note: To be eligible, participants taking CYP inhibitors (e.g., zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose. Note: CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider. * Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions. * 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.
- Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (i.e., nephrectomy) within 4 weeks prior to first dose of study treatment. Minor surgery (e.g., simple excision, tooth extraction) within 5 days before first dose of study treatment. Complete wound healing from major or minor surgery must have occurred at least prior to first dose of study treatment. * Note: Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms 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.
- History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.
- Pregnant or lactating females.
- Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube.
- Previously identified allergy or hypersensitivity to components of the study treatment formulations.
- Another malignancy that requires active therapy and in the opinion of the Investigator would interfere with monitoring of radiologic assessments of response to Investigational Product, 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.
- Other conditions, which in the opinion of the Investigator, would compromise the safety of the patient or the patient’s ability to complete the study.
Additional locations may be listed on ClinicalTrials.gov for NCT06795009.
Locations matching your search criteria
United States
Missouri
Saint Louis
PRIMARY OBJECTIVE:
I. To identify the recommended phase 2 dose (RP2D) of zanzalintinib in combination with paclitaxel given on a 21-day schedule in this patient population.
SECONDARY OBJECTIVES:
I. To determine the overall safety and tolerability of zanzalintinib in combination with paclitaxel given on a 21-day schedule in this patient population.
II. To determine the overall response rate (ORR) of zanzalintinib in combination with paclitaxel for treating recurrent high grade uterine cancer.
III. To determine the progression-free survival (PFS) of patients with recurrent high grade uterine cancer who receive zanzalintinib in combination with paclitaxel.
IV. To determine the overall survival (OS) of zanzalintinib in combination with paclitaxel in recurrent high grade uterine cancer.
EXPLORATORY OBJECTIVES:
I. To compare response rates in patients with high or low pre-treatment tumor AXL expression.
II. To evaluate blood pharmacokinetics (PK) of zanzalintinib in combination with paclitaxel given on a 21-day schedule in this patient population.
III. To evaluate blood pharmacodynamics (PD) of zanzalintinib in combination with paclitaxel given on a 21-day schedule in this patient population, by assessing plasma biomarkers of mechanism of action and clinical activity (VEGF, VEGFR2, CRP, HGF, IL8, GAS6, Rantes, and Granzyme B).
OUTLINE: This is a phase I/Ib dose-escalation study of zanzalintinib in combination with paclitaxel followed by a dose-expansion study.
Patients receive zanzalintinib orally (PO) once daily (QD) on days 1-21 of each cycle and paclitaxel intravenously (IV) over 3 hours on day 1 of each cycle. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with complete response (CR) after 6 cycles of zanzalintinib + paclitaxel treatment receive zanzalintinib alone every 21 days in the absence of disease progression or unacceptable toxicity. Patients with partial response (PR) or stable disease (SD) after 6 cycles continue zanzalintinib + paclitaxel treatment for an additional 3 cycles in the absence of disease progression or unacceptable toxicity. After 9 cycles of zanzalintinib + paclitaxel treatment, patients with PR or SD receive zanzalintinib alone every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine collection, as well as computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study. Patients may undergo tumor biopsy during screening.
After completion of study treatment, patients are followed up at 14 and 28 days, then every 3 months for 2 years, followed by every 6 months for years 2-5.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorDavid Gardner Mutch
- Primary ID202503049
- Secondary IDsNCI-2025-02987
- ClinicalTrials.gov IDNCT06795009