A Phase I Study of d-Limonene With Concurrent Radiation and Platinum Based Chemotherapy for Xerostomia Prevention in Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Stanford University
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Dose limiting Toxicity
Study Overview
Brief Summary
This study explores the safety of d-limonene, a commercially-available dietary supplement (food) as a potential therapeutic for the severe dry mouth (xerostomia) experienced by patients with head and neck cancer as a side effect of their anti-cancer treatment.
Detailed Description
Primary Objective:To determine the maximum tolerated dose (MTD) of d limonene when combined with radiation and platinum based chemotherapy in subjects with loco regionally advanced head and neck squamous cell carcinoma (HNSCC) based upon dose limiting toxicity (DLT)
Secondary Objective:
- To evaluate the feasibility and subject compliance with adjuvant administration of d limonene daily up to a maximum of 4 months after completion of chemoradiation
- To correlate the level of d-limonene measured in the plasma to the dose levels(s) administered to the subject
- To correlate the level of d limonene measured in the plasma to saliva flow rate and xerostomia questionnaire scores in subjects enrolled in this trial
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Supportive Care
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically or cytologically confirmed diagnosis of advanced loco regional squamous cell carcinoma of the nasopharynx (AJCC v8 Stage II IV); oropharynx (AJCC v8 Stage I III for HPV+ cancer, excluding T1 2N0; AJCC v8 Stage III IV for Human papillomavirus (HPV) negative cancer); larynx (AJCC v8 Stage III to IV); or hypopharynx (AJCC v8 Stage III to IV), scheduled to undergo chemoradiation. Patients with squamous cell carcinoma of the head and neck from an unknown primary site with involved nodes (N1 to 3) also qualify.
- •Scheduled to received definitive RT with concurrent platinum based chemotherapy at Stanford
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1
- •Must be able to swallow d limonene gelcaps at the time of enrollment.
- •Adequate hepatic function within 2 weeks prior to registration defined as follows: Bilirubin ≤ 2 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 times the upper limit of normal
- •Adequate hematologic function within 2 weeks prior to registration defined as follows:
- •Absolute neutrophil count (ANC): ≥ 1,500/mm3
- •Platelets: ≥ 100,000/mm3
- •Hemoglobin: ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable).
- •Adequate renal function defined as follows:
- •Serum creatinine ≤ 1.5 mg/dL within 2 weeks prior to registration or creatinine clearance (CC) ≥ 50 mL/min within 2 weeks prior to registration determined by 24 hour collection or estimated by Cockcroft Gault formula:
- •CCr male = [(140 - age) x (wt in kg)] [(Serum Cr mg/dL) x (72)] CCr female = 0.85 x (CrCl male)
- •Negative serum pregnancy test within 2 weeks prior to registration and agreement to use a birth control method during the entire duration of d limonene treatment for women of childbearing potential
- •Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- •History of allergic reactions attributed to citrus fruits
- •Pregnant or lactating
Arms & Interventions
d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
d-limonene -8gram
8 gram d-limonene orally, as 4 grams 2 times daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
d-limonene -8gram
8 gram d-limonene orally, as 4 grams 2 times daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
de-escalation dose d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
de-escalation dose d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
de-escalation dose d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
de-escalation dose d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
de-escalation dose d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: Intensity modulated radiotherapy (IMRT) (Radiation)
de-escalation dose d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: Xerostomia questionnaire (Other)
d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
d-limonene -8gram
8 gram d-limonene orally, as 4 grams 2 times daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
de-escalation dose d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
de-escalation dose d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
de-escalation dose d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: D-Limonene Gelcaps (Drug)
d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
d-limonene -8gram
8 gram d-limonene orally, as 4 grams 2 times daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
de-escalation dose d-limonene -6gram
6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
de-escalation dose d-limonene -4gram
4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
de-escalation dose d-limonene -2gram
2 gram d-limonene orally, once daily delivered during chemoradiation
Intervention: Cisplatin (Drug)
Outcomes
Primary Outcomes
Dose limiting Toxicity
Time Frame: 9 weeks
Dose limiting toxicity is defined as d-limonene related toxicity causing: * Greater than 1 week delay in completing the radiation course. * Inability to receive ≥ 66 Gy of radiotherapy. * Inability to receive at least 200 mg/m2 of total cisplatin equivalent dose or a total area under the curve (AUC) of 10 for carboplatin equivalent dose due to toxicity related to d-limonene Grade 3 or higher diarrhea that is attributable to the study drug. * Grade 3 abdominal pain that is attributable to the study drug. The outcome will be reported as the number of participants per dose level who experience any DLT (a number without dispersion / variance).
Secondary Outcomes
- Feasibility of adjuvant d-limonene administration(4 months)
- Xerostomia toxicity(12 months post completion of chemoradiation)