Phase Ib Study of Alpelisib With Cisplatin in Patients With HPV+ Solid Tumor Malignancies

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose and recommended phase 2 dose of alpelisib in
combination with weekly cisplatin.

SECONDARY OBJECTIVES:

I. To determine the objective response rate and median progression-free survival with the
treatment combination in HPV positive (+) solid tumor malignancies.

II. To characterize the safety profile of the combination.

OUTLINE: This is a dose escalation study.

Patients receive alpelisib orally (PO) once daily (QD) on days 1-14 or 1-21, and cisplatin
intravenously (IV) over 1-2 hours on days 1 and 8, or days 1, 8, and 15. Courses repeat every
21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Able to understand and voluntarily sign the informed consent form, and able to comply
with the study visit schedule and other protocol requirements. Written informed
consent obtained prior to any screening procedures.

- Age ≥ 18 years.

- Dose escalation:

- Any locally advanced or metastatic solid tumor malignancy with no curative treatment
options available

- Dose expansion:

- HPV-associated locally advanced or metastatic platinum-resistant solid tumor
malignancy. HPV positivity defined by positive p16 immunohistochemistry or in-situ
hybridization assessment of archival tissue (primary or metastatic) in a
CLIA-certified laboratory. Availability of pathology report from CLIA-certified lab
demonstrating positive HPV status by p16 IHC or in situ hybridization qualifies for
eligibility determination. Analysis of fresh tumor tissue is permitted in cases where
archival tissue is not available.

- Platinum resistance defined as prior progression (radiographic or clinical) either
during or within 6 months following completion of platinum-based chemotherapy.

- Platinum-based therapy as most recent systemic therapy prior to enrollment allowed but
not required

- Patients may have received any number of lines of prior systemic therapy for locally
advanced/metastatic disease.

- Eastern Cooperative Oncology Group performance status ≤ 1

- Patient has adequate bone marrow and organ function as defined by the following
laboratory values:

- Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L

- Platelet count ≥ 100 x 10^9/L

- Hemoglobin ≥ 9.0 g/dL

- Serum creatinine < 1.5 x ULN OR Estimated GFR by Cockroft-Gault equation OR 24 hour
urine collection ≥ 60 ml/min

- Total serum bilirubin ≤ 1.5 x ULN (< 3 x ULN in patients with documented/suspected
Gilbert's disease with concomitant direct bilirubin ≤ 1.5 x ULN)

- Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 2.5 x ULN (or ≤
5 x ULN if liver metastases are present)

- Fasting plasma glucose (FPG) ≤ 140mg/dL or 7.8 mmol/L

- Hemoglobin A1c < 7%

- Patient is able to swallow oral medications.

- Measurable or evaluable disease by RECIST 1.1 in dose escalation. Measurable disease
by RECIST 1.1 is required in dose expansion.

- Recovery from all AEs of previous anti-cancer therapies, including surgery,
chemotherapy and radiotherapy, to baseline or to CTCAE Grade ≤ 1, except for alopecia.

Exclusion Criteria:

- Prior treatment with PI3K-inhibitor.

- Prior known hypersensitivity to any of the excipients of alpelisib.

- Grade ≥ 2 peripheral neuropathy.

- Grade ≥ sensorineural hearing loss.

- Patients with uncontrolled CNS metastatic involvement. However, patients with
metastatic CNS tumors may participate in this study if the patient is:

- > 4 weeks from prior therapy completion (including radiation and/or surgery) to
starting the study treatment

- Clinically stable with respect to the CNS tumor at the time of screening

- Not receiving steroid therapy

- Not receiving anti-convulsive medications that were started for brain metastases.

- Patients who have received prior systemic anti-cancer treatment within 4 weeks or 5
half-lives of prior to starting study treatment, whichever is shorter.

- Prior investigational therapy within 4 weeks of start of study treatment.

- Patients who have received radiotherapy ≤ 2 weeks prior to starting study drugs, with
exception of palliative radiotherapy, who have not recovered from side effects of such
therapy to baseline or Grade ≤ 1 and/or from whom ≥ 30% of the bone marrow was
irradiated.

- Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH), or fondaparinux is allowed

- Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment
or who have not recovered from side effects of such procedure.

- Clinically significant cardiac disease or impaired cardiac function, such as:

- Congestive heart failure (CHF) requiring treatment (New York Heart Association (NYHA)
Grade ≥ 2) or left ventricular ejection fraction (LVEF) < 50% as determined by
multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening

- History or current evidence of clinically significant cardiac arrhythmias, atrial
fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-
grade/complete AV-blockage

- Acute coronary syndromes (including myocardial infarction, unstable angina, coronary
artery bypass graft [CABG], coronary angioplasty, or stenting), < 3 months prior to
screening

- QT interval adjusted according to Fredericia (QTcF) > 480 msec on screening ECG

- Patients with diabetes mellitus requiring insulin treatment or uncontrolled
steroid-induced diabetes mellitus.

- Any other condition that would, in the Investigator's judgment, preclude patient's
participation in the clinical study due to safety concerns or compliance with clinical
study procedures, e.g. infection/inflammation, intestinal obstruction,
social/psychological complications.

- Impaired GI function or GI disease that may significantly alter the absorption of oral
alpelisib (e.g. Uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or
significant small bowel resection).

- Patients who are currently receiving medication with a known risk of prolonging the QT
interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be
discontinued or switched to a different medication prior to starting study drug
treatment. A list of prohibited drugs with a known risk of TdP is provided in
Appendix.

- Patient is currently receiving treatment with drugs known to be strong inhibitors or
inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at
least one week and must have discontinued strong inhibitors before the start of
treatment. Switching to a different medication is allowed. (Refer to Appendix)

- Known positive serology for human immunodeficiency virus (HIV) (baseline testing not
required)

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/mL)

- 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
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.