This is a Phase Ib dose escalation / expansion study with the combination of alpelisib and weekly cisplatin. Dose escalation will follow standard 3+3 design. During dose escalation, two dose levels of weekly cisplatin (30 and 35 mg/m2, respectively) will be evaluated in combination with escalating doses of alpelisib in parallel. Cohort B (cisplatin 35 mg/m2) at a given dose level of alpelisib to open only after corresponding A cohort (cisplatin 30 mg/m2) at the same dose level of alpelisib has cleared DLT window. Cohorts A and B may enroll in parallel (e.g., Cohort 3A may enroll in parallel with Cohort 2B) as shown below in the dose escalation schema. Intermediate dose levels and alternative dosing schedules may be investigated per the discretion of Principal Investigator using same 3+3 dose escalation schema (e.g. cisplatin administered days 1, 8 of 21 day cycle).
A Phase Ib, Open-label Study of Alpelisib (BYL719) in Combination With Cisplatin in Patients With HPV+ Solid Tumor Malignancies
The starting dose of alpelisib at 200 mg once daily was chosen based upon the aggregate of safety, PK, and efficacy data shown above, indicating:
The investigators will escalate at 50 mg increments per dose level, up to a maximum dose of 350 mg daily. Though the single agent MTD/RP2D of alpelisib is 400 mg, in combination with a variety of targeted therapies the MTD/RP2D is in the range of 300-350 mg daily.
The investigators chose a weekly cisplatin dosing schedule which has demonstrated activity in squamous cell carcinoma of the head and neck and cervix. Both 30 and 35 mg/m2 of cisplatin weekly have been shown to have activity in HNSCC and other squamous cell histologies, and the investigators will investigate both dose levels in combination with alpelisib as shown in section 3 of the protocol.
Solid Tumors HPV+ Cisplatin
Open to people ages 18 years and up
4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment:
Sexually active males should use a condom during intercourse while taking drug and for 16 weeks after the final dose of study treatment and should not father a child in this period, but may be recommended to seek advice on conservation of sperm. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through at least 16 weeks after the final dose of study treatment. Highly effective contraception is defined as either:
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception].
Female sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female study subjects, the vasectomized male partner should be the sole partner for that patient].
Use a combination of the following (both a+b):
Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not allowed as alpelisib may decrease the effectiveness of hormonal contraceptives.
Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.
For women with therapy-induced amenorrhea, oophorectomy or serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status.
NOTE: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH)agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
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