| Eligibility |
Inclusion Criteria - phase II only
1. Histologically or cytological confirmed diagnosis of Rb-deficient HNSCC for which no
standard curative therapy is available.
2. Rb deficient HNSCC includes CLIA-certified testing confirming one of the following:
A. HPV positive as determined by any one of the following: p16 immunohistochemistry (IHC),
HPV RNA in situ hybridization (ISH), RNAscope (mRNA ISH), DNA ISH, DNA PCR, or qRT PCR.
B. No Rb protein expression in the tumor as determined by IHC.41, 48 3. Progression on
prior treatment with an anti-PD-1 antibody or an anti-PD-L1 antibody.
A. Has received at least 2 doses of a PD-1/PD-L1 checkpoint blockade therapy. B. Clinical
or radiographical progression has been documented within 12 weeks from the last dose of
PD-1/PD-L1 checkpoint blockade therapy.
Inclusion Criteria - phase I only
1. Histologically or cytological confirmed diagnosis of an invasive solid tumor malignancy,
for which no standard curative or life prolonging therapy is available.
Inclusion Criteria - both phase I and phase II
1. Male or female patients = 18 years of age.
2. ECOG performance status of = 2 (see section 7.4).
3. Clinical laboratory values as specified below within 22 days before the first dose of
study drug
- Absolute neutrophil count (ANC) > 1500/mm³
- Platelets > 100,000/mm³
- Hgb > 9 g/dL. Values must be obtained without need for myeloid growth factor or
platelet transfusion support within 14 days, however, erythrocyte growth factor
is allowed as per published ASCO guidelines.
- Total bilirubin = 1.5 x upper limit of normal (ULN)
- SGOT (AST) and SGPT (ALT)< 2.5 x ULN. AST and/or ALT may be up to 5X ULN if with
known liver mets or total 3 x ULN with direct bilirubin = ULN in patients with
well-documented Gilbert syndrome.
- Adequate renal function as defined by calculated creatinine clearance =30 ml/min
(Cockroft-Gault Formula, see Section 7.5).
4. Measurable disease according to RECIST version 1.1.
5. Voluntary written consent must be given before performance of any study related
procedure not part of standard of care, with the understanding that consent may be
withdrawn by the patient at any time without prejudice to future medical care.
6. Patients must be able to either swallow alisertib enteric coated tablets, swallow
alisertib oral solution formulation, or administer alisertib oral solution formulation
via a feeding tube that terminates in the stomach.
7. Willing to provide blood and tissue for correlative research purposes.
8. Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 1 highly effective
method of contraception and 1 additional effective (barrier) method at the same
time, from the time of signing the informed consent through 120 days after the
last dose of study drug, OR
- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)
9. Male patients, even if surgically sterilized (i.e., status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study
treatment period and through 120 after the last dose of study drug, OR
- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, postovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)
Exclusion Criteria:
1. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
considered to be over 25%.
2. Prior allogeneic bone marrow or organ transplantation.
3. Known gastrointestinal (GI) disease or GI procedures that could interfere with the
oral absorption or tolerance of alisertib. Examples include, but are not limited to
partial gastrectomy, history of small intestine surgery, and celiac disease.
4. Inability to swallow (or use a feeding tube to administer) oral medication or
inability or unwillingness to comply with the administration requirements related to
alisertib.
5. Known history of uncontrolled sleep apnea syndrome and other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease; requirement for supplemental oxygen.
6. Requirement for constant administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes throughout the study. The intermittent use of H2-antagonists and
antacids (including carafate) is only allowed within these guidelines:
1. H2 antagonists until D-1 and after the dosing of alisertib is done
2. Antacid formulations until 2 hours before doing and after 2 hours following
dosing.
3. PPI is allowed until D-5 of first alisertib dose. PPIs are prohibited throughout
the study
7. Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (see Section 7.3), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities. Prior to study entry, any
ECG abnormality at Screening has to be documented by the investigator as not medically
relevant.
8. Female subject who is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative urine or serum ß-human chorionic
gonadotropin (ß-hCG) pregnancy test result obtained during screening. Pregnancy
testing is not required for post-menopausal or surgically sterilized women.
9. Female patient who intend to donate eggs (ova) during the course of this study or 120
days after receiving their last dose of study drug(s).
10. Male patients who intend to donate sperm during the course of this study or 120 days
after receiving their last dose of study drug(s).
11. Other severe acute or chronic medical or psychiatric condition, including uncontrolled
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement
for pancreatic enzymes, any condition that would modify small bowel absorption of oral
medications, or laboratory abnormality that may increase the risk associated with
study participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for enrollment in this study.
12. Diagnosed or treated for another invasive malignancy within 2 years of enrollment,
with the exception of complete resection of basal cell carcinoma or squamous cell
carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after
curative therapy.
13. Has received any anti-cancer treatment including investigational agents within 21 days
prior to first dose of alisertib.
14. Patients who receive gamma knife radiosurgery for brain metastases or whole brain
radiation are eligible if gamma knife radiosurgery was completed > 2 weeks before
treatment is started or whole brain radiation was performed > 4 weeks before treatment
is started, and are clinically stable (not requiring steroids or anti-epileptic
drugs).
15. Known hypersensitivity to any of the excipients of alisertib enteric coated tablets or
severe reaction to any human monoclonal antibody.
16. Patients with a prior history of clinically significant metabolic acidosis (exclusion
only for patients receiving alisertib oral solution).
17. Major surgery within 28 days prior to first dose of alisertib or persisting side
effects that have not improved to NCI-CTCAE grade 1 or better.
18. Patients who are on (or will require) prolonged systemic corticosteroid treatment
during the study except for replacement dosing for adrenal insufficiency.
19. Concurrent severe and/or uncontrolled medical conditions that would, in the
investigator's judgment, contraindicate patient participation in the clinical study or
require concomitant anti-cancer drugs (e.g. active or uncontrolled severe infection,
chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis,
uncontrolled high blood pressure, interstitial lung disease).
20. Patients with active, known, diagnosed or suspected autoimmune disease. Patients
suffering from vitiligo, type I diabetes mellitus, residual hypothyroidism due to
autoimmune thyroiditis only requiring thyroid hormone replacement therapy, or
psoriasis not requiring systemic treatment can be enrolled.
21. Patients diagnosed with active interstitial lung disease (ILD)/pneumonitis or a
history of ILD/pneumonitis or another condition requiring immunosuppressive doses of
systemic medication such as systemic corticosteroids or absorbed topical
corticosteroids (doses = 10 mg/day prednisone or equivalent) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical corticosteroids, adrenal replacement doses, or < 10 mg daily prednisone or
equivalent are permitted.
22. Administration of any live vaccine within 30 days before first dose of study drug.
23. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus or
hepatitis C virus, except for: Patients with HIV who have controlled infection
(undetectable viral load and CD4 count above 350 cells/mm3 either spontaneously or on
a stable antiviral regimen) are permitted; Patients with hepatitis B (HepBsAg+) virus
who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit
of detection AND receiving antiviral therapy for hepatitis B) are permitted; Patients
who are hepatitis C virus antibody positive (HCV Ab +) who have controlled infection
(undetectable HCV RNA by PCR either spontaneously or in response to a successful prior
course of anti-HCV therapy) are permitted.
24. Participating in another therapeutic clinical trial.
25. Prior immune-related adverse events (irAE) as follows:
A. Any life-threatening irAE will not be eligible.
B. Any grade irAE of the following types will not be eligible:
- i. Nervous system irAE
- ii. Ocular irAE
- iii. Cardiovascular irAE
- iv. Severe Cutaneous Adverse Reactions (SCAR)
- v. Hematological irAE
C. Any grade endocrine irAE will be eligible if replacement therapy can compensate for the
resulting deficit.
D. Grade = 2 irAE of the following will not be eligible:
- i. Colitis
- ii. Hepatitis
- iii. Bullous Dermatoses
- iv. Pneumonitis
- v. Musculoskeletal
- vi. Renal
E. Grade = 3 cutaneous irAE will not be eligible.
F. All irAEs must have resolved to Grade = 1 at least 14 days before the planned first
dose.
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