Phase Ib Study of BKM120 With Cisplatin and XRT in High Risk Locally Advanced Squamous Cell Cancer of Head and Neck

Phase 1

Completed

• Conditions: Carcinoma, Squamous Cell of Head and Neck; Carcinoma of Larynx; Early Invasive Cervical Squamous Cell Carcinoma; HPV Positive Oropharyngeal Squamous Cell Carcinoma; Hypopharyngeal Cancer; Cancer of Nasopharynx
• Interventions: Drug: BKM120; Drug: Cisplatin; Radiation: Intensity-modulated radiotherapy (IMRT)

• Registration Number: NCT02113878
• Lead Sponsor: Dana-Farber Cancer Institute

Brief Summary

This research study is evaluating a drug called buparlisib (BKM120) as a possible treatment for locally advanced head and neck squamous cell cancer.

Detailed Description

* This phase Ib study is combining standard chemoradiotherapy with weekly cisplatin and BKM120 to assess tolerability of this combination in high risk patients with locally advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN). The investigators will also obtain preliminary information about the efficacy of this treatment.

* The participant will receive the study drug buparlisib once daily, by mouth, for 45 days. The participant will be given a study drug-dosing diary for each cycle. It will include special instructions for taking the study drug at home.

* The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects, not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study before and how well they have tolerated their doses.

* All participants will receive weekly cisplatin injection. Cisplatin will be given intra-venously (IV) on days: (1, 8, 15, 22, 29, 36 and 43) at DFCI.

* All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks, delivered at DFCI. IMRT is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor.

* The investigators would like to keep track of the participant's medical condition. Follow-up will continue every 4 to 12 weeks after the end of treatment for the first year and at the investigator's discretion thereafter.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2014-04-01
• Study First Submitted QC: 2014-04-11
• Study First Posted: 2014-04-15
• Study Start: 2014-09-29
• Primary Completion: 2019-12-06
• Study Completion: 2022-01-01
• Results First Submitted: 2022-04-11
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-01
• Last Update Submitted: 2024-11-01
• Results First Posted: 2024-11-05
• Last Update Posted: 2024-11-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

• Stage III/IV, locally advanced, biopsy proven squamous cell cancer of the head and neck that undergo chemoradiation as their primary treatment with curative intent.
• Oropharynx (HPV positive and HPV negative), hypopharynx, larynx primaries, nasopharynx as well as those with documented SCC of the cervical lymph nodes, with unknown primaries.
• >10 pack years of tobacco use
• Age ≥ 18 years
• ECOG performance status ≤ 2
• At least one site of measurable disease
• Adequate bone marrow function as shown by: ANC > 1.5 x 109/L, Platelets >100 x 109/L, Hb >9 g/dL
• Total calcium (corrected for serum albumin) within normal limits
• Magnesium ≥ the lower limit of normal
• Potassium within normal limits for the institution.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range
• Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome)
• Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min
• Serum amylase ≤ ULN
• Serum lipase ≤ ULN
• Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)
• Signed informed consent
• INR ≤ 2

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Exclusion Criteria

• Distant metastatic disease
• Less than or equal to 10 pack years of tobacco history
• Received prior chemotherapy
• Received prior radiation to the head and neck or adjacent anatomical site
• Received prior treatment with a P13K inhibitor.
• Known hypersensitivity to BKM120 or to its excipients
• Acute or chronic liver, renal disease or pancreatitis
• Mood disorders ≥ CTCAE grade 3
• Diarrhea ≥ CTCAE grade 2
• Active cardiac disease
• History of cardiac dysfunction including any of the following:
• Patient has poorly
• Impairment of gastrointestinal (GI) function
• Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug.
• Chronic treatment with steroids or another immunosuppressive agent.
• Herbal medications and certain fruits within 7 days prior to starting study drug.
• Currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. Please refer to Appendix B for a list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with weak inhibitors of CYP3A is allowed).
• Undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
• Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant.
• Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control.
• Known diagnosis of human immunodeficiency virus (HIV) infection
• History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dose Level 1	BKM120	* 40 mg BKM120 will be administered orally daily for 45 days. Starting dose 40 mg. * Cisplatin: Starting Dose 30 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). * Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.
Dose Level 1	Cisplatin	* 40 mg BKM120 will be administered orally daily for 45 days. Starting dose 40 mg. * Cisplatin: Starting Dose 30 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). * Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.
Dose Level 1	Intensity-modulated radiotherapy (IMRT)	* 40 mg BKM120 will be administered orally daily for 45 days. Starting dose 40 mg. * Cisplatin: Starting Dose 30 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). * Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.
Dose Level 2	BKM120	* 40 mg BKM120 will be administered orally daily for 45 days. * Cisplatin: Starting Dose 35 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). * Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.
Dose Level 2	Cisplatin	* 40 mg BKM120 will be administered orally daily for 45 days. * Cisplatin: Starting Dose 35 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). * Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.
Dose Level 2	Intensity-modulated radiotherapy (IMRT)	* 40 mg BKM120 will be administered orally daily for 45 days. * Cisplatin: Starting Dose 35 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). * Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of Cisplatin	While on treatment, up to 66 days	The trial uses 3+3 design to determine maximum tolerated dose (MTD).
Maximum Tolerated Dose of BKM120	While on treatment, up to 66 days	The trial uses 3+3 design to determine maximum tolerated dose (MTD).

Secondary Outcome Measures

Name	Time	Method
24 Month Overall Survival	Up to 24 months	The probability of survival at 24 months using Kaplan-Meier estimates. Patients alive at 2 years are censored at 2 years.
Median Depression Score Change	From baseline to cycle 9, up to 66 days.	The median change in score on the Patient Health Questionnaire - 9 (PHQ-8) from baseline to cycle 9. PHQ-9 has 9 questions and each question has score from 0 to 3. Sum score of all questions will be used as the final score. The final score ranges from 0 to 27. Higher score represents worse depression.
Best Overall Response	Measured at end of treatment, up to 66 days	The best overall response for each patient is given per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1) criteria: Complete Response (CR) - Disappearance of all target and non-target lesions and lymph node short axis is \<10 mm and no new lesions; Partial Response (PR); * Disappearance of target lesions and \>=1 persisting non-target lesion or tumor marker levels above normal limits and no new lesions or; * \>=30% decrease in sum of target lesion diameter and no new lesions; Stable Disease (SD); - Less than 5 mm increase in target lesion diameter unless it results in a \>=20% increase in diameter and \>=1 persisting non-target lesion or tumor marker levels above normal limits and no new lesions; Progressive Disease (PD); * \>20% increase in target lesion diameter, must be an absolute increase of 5mm or; * Substantial worsening in non-target lesion or; * New lesion present
Median Anxiety Score Change	From baseline to cycle 9, up to 66 days.	The median change in score on the Generalized Anxiety Disorder - 7 (GAD-7) questionnaire from baseline to cycle 9.GAD-7 has 7 questions and each question has score from 0 to 3. Sum score of all questions will be used as the final score. The final score ranges from 0 to 21. Higher score represents worse anxiety.
P13K Status by Response	Biopsies drawn up to 10 days from registration. Response measured at from baseline to cycle 9, up to 66 days.	Phosphoinositide 3-kinase (PI3K) biomarker status, either positive or negative, analyzed using established methods from tumor biopsies. P13K status is reported by response, either responder (CR or PR) or non-responder (SD or PR).
Median Time to Progression	Up to 24 months (Progression is defined using RECIST v1.0 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions)	The median amount of time from baseline to progression and/or death. Patients known to be alive at last contact are censored at last contact. All patients alive at 24 months from baseline are censored at 24 months.

Trial Locations

Locations (1)

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States