Background: Head and neck cancers (HNCs) account for about 5% of all cancers worldwide. They grow in the mouth, throat, nasal cavity, or salivary glands. Prostate cancer is the most common cancer in men in the United States. Survival rates for these cancers are lower than 50% if they spread to other parts of the body or return after treatment. Better treatments are needed. Objective: To test a new drug (SX-682), combined with an approved drug (docetaxel, or DTX), in people with HNCs or prostate cancer. Eligibility People aged 18 years and older with an HNC or prostate cancer that has returned after treatment or has spread. Design: Participants will be screened. They will have blood tests, imaging scans, and a test of their heart function. A tissue sample (biopsy) of the tumor may be taken. Participants will take the study drugs in 3-week cycles. SX-682 is a tablet taken by mouth twice a day from Days 1 to 11 of each cycle. Participants will get a supply of the drug to take home. DTX is given on Day 8 of each cycle through a tube attached to a needle inserted into a vein in the arm. Participants will come to the clinic on Days 1 and 8 of every cycle. They will take both drugs for up to 6 cycles. Participants will have follow-up visits 1 week and 1 month after they finish taking the drugs. Follow-ups will continue every 3 months for 2 years. Then they will have phone or email check-ins twice a year until 5 years have passed.
Background * Recurrent and advanced head and neck squamous cell cancers (HNSCC) are treated with systemic chemotherapy plus or minus checkpoint blockade and overall survival ranges between 6 to 15 months. Recurrent/metastatic salivary gland carcinomas (SGC) lack standardized treatment and respond poorly to checkpoint inhibitors. Therefore, both are clear unmet clinical needs. * Docetaxel (DTX) has demonstrated activity in HNSCC and SGC. Preclinical data suggest that DTX increases both innate and adaptive immunity. Increased objective response rate from DTX was seen in patients with HNSCC previously exposed to checkpoint blockade compared to checkpoint-inhibitors na(SqrRoot) ve patients. * Myeloid-derived suppressor cells (MDSCs) promote an immunosuppressive tumor microenvironment and treatment resistance in HNSCC. Preclinical models of head and neck cancers (HNC) show significant neutrophilic-MDSCs infiltrating the tumor, likely recruited through the CXCR1-2 pathway. MDSCs have been described also in some SGC subtypes, associated with lack of immune infiltration. * In preclinical HNSCC models, blockade of CXCR1-2 chemokine receptors by dual allosteric inhibitor SX-682 has demonstrated a marked reduction in MDSCs trafficking to tumors resulting in increased immune effector cell infiltration. Further, SX-682 appears to downregulate tubulin-beta 3, which is reported to be responsible for DTX resistance. * DTX is a standard option in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Despite improvements in survival with DTX, nearly all patients treated with DTX become refractory due to the development of resistance. Rationale combinations with DTX are needed to improve upon current treatments and overcome resistance mechanisms. * In mCRPC, MDSCs remain a major mediator of immunosuppression in the tumor microenvironment. Targeting the CXCR1/2 pathway can be an alternate immunotherapeutic approach in treatment in an otherwise immunosuppressive tumor microenvironment. * As in head and neck cancer (HNC), in prostate cancer models, SX-682 appears to downregulate tubulin-beta 3, which is reported to be responsible for DTX resistance. * DTX in combination with SX-682 is a rational combinational approach for treating HNSCC, SGC, and mCRPC offering potential synergistic activity and the induction/restoration of chemotherapy-sensitivity and immune effector activity. Objectives * Phase I: To determine the recommended phase II dose (RP2D) of SX-682 in combination with DTX in participants with HNSCC, SGC, or mCRPC * Phase II: To determine the efficacy of the combination of SX-682 and DTX in participants with HNSCC or SGC using objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) v 1.1 or in participants with mCRPC using RECIST v1.1 and Prostate Cancer Working Group 3. Eligibility * Age \>= 18 years * Histologically confirmed HNSCC (including oral cavity, oropharynx, larynx, hypopharynx, paranasal sinuses, nasopharynx) or SGC (including adenoid cystic carcinoma \[ACC\] and non-ACC) and recurrent, metastatic (R/M) or advanced incurable disease or mCRPC * Participants with HNSCC or SGC should have received at least 1 standard systemic therapy, or cannot tolerate standard therapy, or there is no standard therapy for their tumor type. * Participants with mCRPC should have received modern anti-androgens. Design * This is a non-randomized, Phase I/II trial to determine the safety and efficacy of DTX in combination with SX-682 in participants with HNSCC, SGC, and mCRPC. * In the Phase I portion of the study, participants will be enrolled in a 3+3 dose escalation schema using 4 SX-682 dose levels and a fixed dose of DTX (Arm 1). * Following identification of RP2D for SX-682, an expansion phase (Phase II) will be initiated, using RP2D SX-682 with a fixed dose of DTX (Arm 2). * DTX will be administered intravenously (IV) on day 8 of each 3-week cycle. * SX-682 will be administered orally twice a day from day 1 to day 11 of each 3-week cycle. * Participants will receive DTX and SX-682 for up to 6 cycles or until disease progression, intolerable side effects, the participant s request to discontinue therapy, or PI decision.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
120
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Phase I: To determine the RP2D of SX-682 in combination with DTX in participants with HNSCC, SGC, or mCRPC
Toxicities will be tabulated and reported according to grade and type of toxicity experienced. Responses will be reported as the proportion of evaluable participants along with a confidence interval.
Time frame: 28 days
Phase II: To determine the efficacy of the combination of SX-682 and DTX in participants with HNSCC or SGC using ORR per RECIST v 1.1 or with mCRPC using RECIST v1.1 and Prostate Cancer Working Group 3
Overall response rate (ORR) as defined by the proportion of participants who achieve a response (CR+PR) will be reported separately for each, along with 95% and 80% confidence intervals (Clopper-Pearson).
Time frame: Assessment at baseline, C4D8, 7 days after C6, and then every 3 months until PD or until 2 years after study treatment initiation
To assess safety of SX-682 in combination with DTX
Toxicity will be reported descriptively for each cohort separately.
Time frame: Assessed from the first study treatment, C1D1, through safety visit (28 days post-treatment) or start of new anticancer treatment, whichever comes first.
To assess progression free survival (PFS)
PFS will be determined separately by cohort using Kaplan-Meier plots. Medians and 95% confidence intervals will be provided for each of these secondary objectives. PFS will be determined separately for 6, 12 and 24 months.
Time frame: Assessed at C1D1, C4D8, 7 days after C6, and then every 3 months until PD or until 2 years after study treatment initiation.
To assess overall survival (OS)
OS will be determined separately by cohort using Kaplan-Meier plots. Medians and 95% confidence intervals will be provided for each of these secondary objectives. OS will be determined separately for 2 and 5 years.
Time frame: Assessed at C1-6D1, at the 28-day Safety visit; every 3 months until disease progression or 2 years after start of study treatment; every 6 months after disease progression until 5 years after start of study treatment.
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