Docetaxel and SX-682 in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma, Salivary Gland Carcinoma, and Advanced Prostate Cancer

Phase I/II Trial of Docetaxel and SX-682 in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma, Salivary Gland Carcinoma, and Advanced Prostate Cancer

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Cancer; Nasopharyngeal Carcinoma; Hypopharyngeal Cancer; Adenoid Cystic Carcinoma; Prostate Cancer; Head and Neck Squamous Cell Carcinoma; Oropharyngeal Squamous Cell Carcinoma; Oral Squamous Cell Carcinoma; Salivary Gland Cancer; Paranasal Sinus Neoplasms; Metastatic Castration Resistant Prostate Cancer; Carcinoma of Larynx
• Intervention / Treatment: Drug: SX-682; Drug: DTX

Detailed Description

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
• Enrollment (Estimated): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Michele L Reed, R.N.; Phone Number: (240) 760-6121; Email: michele.reed@nih.gov
• Study Contact Backup: Name: Charalampos Floudas, M.D.; Phone Number: (240) 474-1575; Email: charalampos.floudas@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
      • Contact: National Cancer Institute Referral Office; Phone Number: 888-624-1937; Email: NCIMO_Referrals@mail.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

All Participants

• Age >= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) <= 2

• Participants must have adequate organ and marrow function as defined below:

  • ANC >= 1,500/mcL
  • Hemoglobin (Hgb) >= 9 g/dL
  • Platelets (PLTs) >= 100,000/mcL
  • Creatinine clearance >= 50 mL/min (by Cockroft-Gault formula)
  • Total bilirubin <= 1.5 x iULN (<= 3 x ULN in participants with known/suspected Gilbert s disease)
  • ALT/AST <= 2.5 x iULN
  • Activated partial thromboplastin time (aPTT) <= 1.5 x iULN
• Contraception as follows:
• Women of child-bearing potential (WOCBP) must agree to use an effective method of contraception (barrier, hormonal, intrauterine device [IUD], surgical sterilization, abstinence) prior to study entry, for the duration of study treatment, and for up to 2 months after discontinuation of the study drugs. A participant may request a male partner to use an effective form of contraception to fulfill this requirement.
• Men able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the study treatment and up to 4 months after discontinuation of the study drugs. A participant may request a female partner to use an effective form of contraception to fulfill this requirement. Men able to father a child must not freeze or donate sperm within the same period.
• Nursing participants must be willing to discontinue nursing from study treatment initiation through one week after the last dose of study drugs.
• Participants must be able to swallow oral medications.
• Human immunodeficiency virus (HIV)-infected participants must have undetectable viral load (VL) and be on effective anti-retroviral therapy within 4 weeks prior to the study treatment initiation and have no history of opportunistic infections or Castleman s disease within 12 months prior to the study treatment initiation.
• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV VL.
• Participants with evidence of chronic hepatitis C virus (HCV) infection must have undetectable HCV VL.
• Participants must be able to understand and willing to sign a written informed consent document.

Participants with HNC

• Histologically confirmed HNSCC (including oral cavity, oropharynx, larynx, hypopharynx, paranasal sinuses, nasopharynx) or SGC (including ACC and non-ACC) and recurrent/metastatic (R/M) or advanced incurable disease.

• Prior treatment as follows:

  • Participants with R/M HNSCC must have prior systemic treatment (platinum-based chemotherapy and/or anti-PD(L)1 treatment).
  • Participants with R/M SGC may have any number of prior systemic treatment lines; prior systemic treatment not required for participation.
  • Participants must not have received systemic anticancer treatment within 3 weeks prior to first treatment administration. Note: Treatment-related toxicities must have resolved to Grade <2 or be minimal and not constitute a safety risk. Participants with SGC previously treated with hormonal therapies (e.g., drugs targeting the androgen receptor) may continue these drugs concomitantly with study therapy. Participants with bone metastases or hypercalcemia on intravenous bisphosphonate medications, denosumab, or similar agents, are eligible to participate and may continue this treatment.
• Presence of >= 1 measurable lesion by RECIST v 1.1 criteria.

Participants with mCRPC

• Documented histopathological confirmation of prostate cancer. If no pathologic report or specimen is available, participants may enroll with a history of clinical course consistent with the disease.
• Participants must have mCRPC, defined as at least one lesion on TC-99 bone scan or at least one lesion that is measurable per RECIST 1.1.
• Participants must need ADT as part of their cancer therapy (unless previous orchiectomy)
• Castrate testosterone level (<50 ng/dl or 1.7 nmol/L)

• Prior treatment as follows:

  • DTX for mCRPC is allowed but participants must not have had progression while on docetaxel or within 3 months after completing DTX for mCRPC
  • Participants must have been previously treated with modern anti-androgens such as abiraterone, enzalutamide, apalutamide, or darolutamide.
• Progression defined as two consecutive rising PSA values at least 1 week apart or radiographic evidence of progression seen on computed tomography (CT) scan or TC- 99 bone scan.
• Toxicities related to prior therapy, including surgery and/or radiation, must have resolved to < Grade 1 per CTCAE v.6.0.

EXCLUSION CRITERIA:

All participants

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to DTX, SX-682, or other agents used in study (e.g., polysorbate 80).
• Known active brain metastases. Note: Participants with previously treated brain metastases are eligible if imaging at least four weeks prior to first trial treatment shows no evidence of progression and neurologic symptoms have resolved, have no new or enlarging brain metastases, and are not using glucocorticoids for at least a week prior to first trial treatment
• Participants must not have received other investigational agents within 3 weeks prior to the first dose of the study drug(s).
• Participants must not have received major surgery within 14 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted). If participant underwent major surgery, they must have recovered adequately (according to the Principal Investigator) from the toxicity and/or complications from the intervention prior to starting study treatment.
• Treatment (systemic) with any medications or substances that are moderate or strong inducers or moderate or strong inhibitors of cytochrome P450 (CYP3A4) listed at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions- table-substrates-inhibitors-and-inducers#table2-2,table3-3,table5-2 within 2 weeks or 5 half-lives (whichever is shorter) prior to the start of the study treatment.
• Prior or concurrent malignancy whose natural history or treatment has potential to interfere with the safety or efficacy assessment of the study treatment.
• Participants with serious uncontrolled intercurrent illness evaluated by medical history, electrocardiogram (EKG), and physical exam that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study or that would limit compliance with study requirements.

Participants with HNC

• Participants must not have received large-field radiotherapy within 2 weeks prior to first treatment administration. All residual treatment-related toxicities must have resolved to Grade <2 (except for radiation-induced xerostomia/dysgeusia) or be minimal and not constitute a safety risk.
• Positive pregnancy serum or urine beta-human chorionic gonadotropin (beta-hCG) test

Participants with mCRPC

• Use of other medications for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (e.g., phytoestrogens and saw palmetto) within 1 week prior to the study treatment initiation.
• Cancer related neuropathy at screening
• Baseline QTcF >= 470 ms

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Escalating doses of SX-682 + DTX	Drug: SX-682; SX-682 will be given orally (PO) twice a day at the dose of the corresponding dose level group (for Phase I) or at RP2D (for Phase II).; Drug: DTX; DTX will be administered IV at 75 mg/m^2 over about 60 minutes
Experimental: Arm 2; SX-682 at RP2D + DTX	Drug: SX-682; SX-682 will be given orally (PO) twice a day at the dose of the corresponding dose level group (for Phase I) or at RP2D (for Phase II).; Drug: DTX; DTX will be administered IV at 75 mg/m^2 over about 60 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	Assessment at baseline, C4D8, 7 days after C6, and then every 3 months until PD or until 2 years after study treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess safety of SX-682 in combination with DTX	Toxicity will be reported descriptively for each cohort separately.	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.	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.	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.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Charalampos Floudas, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): July 7, 2026
• Primary Completion (Estimated): October 1, 2036
• Study Completion (Estimated): October 1, 2037

Study Registration Dates

• First Submitted: June 24, 2026
• First Submitted That Met QC Criteria: June 24, 2026
• First Posted (Actual): June 25, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: July 1, 2026
• Last Verified: June 22, 2026

More Information

Terms related to this study

• Keywords: Carcinoma; Chemotherapy; Prostate; Solid Tumors; Head and Neck; Infusion; molecule inhibitor
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Mouth Diseases; Stomatognathic Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Nose Diseases; Otorhinolaryngologic Diseases; Salivary Gland Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Carcinoma, Squamous Cell; Laryngeal Diseases; Nasopharyngeal Neoplasms; Paranasal Sinus Diseases; Mouth Neoplasms; Nose Neoplasms; Nasopharyngeal Carcinoma; Squamous Cell Carcinoma of Head and Neck; Prostatic Neoplasms; Carcinoma; Head and Neck Neoplasms; Laryngeal Neoplasms; Carcinoma, Adenoid Cystic; Salivary Gland Neoplasms; Hypopharyngeal Neoplasms; Paranasal Sinus Neoplasms
• Other Study ID Numbers: 10002319; 002319-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing.
• IPD Sharing Time Frame: Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.
• IPD Sharing Access Criteria: Clinical data will be made available upon request and with the permission of the study Pl. Genomic data are made available via dbGAP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No