This research study is an open-label Phase I clinical trial, which tests the safety of an
investigational drug or combination of investigational drugs and also tries to define the
appropriate dose of the investigational drug(s) to use for further studies. "Investigational"
means that the drug is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved Palbociclib for the
participant specific disease but it has been approved for other uses. The FDA has not
approved Gedatolisib alone or in combination with Palbociclb as a treatment option for the
participant's disease.
In this research study the investigators hope to determine if treatment with Palbociclib and
Gedatolisib will be tolerated and will help to shrink or stop the growth of the participant's
cancer. Palbociclib is an oral drug which has been shown to stop the cell cycle, which is the
way a cell initiates growth. Gedatolisib is thought to work by controlling a series of events
directing cell growth and survival. Gedatolisib may work to stop or slow activity within
tumor cells. By putting these two drugs together the investigators hope that it will have a
greater effect on cancer growth than either drug alone.
Inclusion Criteria:
- For Part I, participants must have histologically confirmed malignancy that is
metastatic or unresectable and resistant to standard therapy or for which no standard
therapy is available. For Part II, participants must have histologically confirmed
advanced squamous cell lung cancer, advanced pancreatic cancer, advanced head & neck
cancer (specifically non-oropharynx squamous cell carcinoma or HPV-negative oropharynx
squamous cell carcinoma), or any tumor with suspected PI3K-pathway dependence (either
by mutation or by known biologic rationale, such as endometrial cancer. PI3K
dependence includes the presence of a PIK3CA-mutant hotspot mutation, PIK3CA copy
number gain, or PTEN loss in the archival or fresh tumor tissue specimen identified in
a CLIA-certified laboratory. All genetic findings must be reviewed by the study PI,
prior to study entry.)
- For Part I, participants are required to have only evaluable disease (disease that is
visible on imaging studies but does not meet RECIST criteria for measurable disease).
For Part II, participants must have measurable disease, defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan.
See section 10 for the evaluation of measureable disease.
- Participants are permitted to have any number of prior therapies prior to enrollment
- Age ≥ 18 years. .
- ECOG performance status ≤ 2
- Participants must have normal organ and marrow function as defined below:
- Absolute neutrophil count ≥ 1,500/mcL
- Hemoglobin ≥9.0 gm/dL
- Platelets ≥ 100,000/mcL
- Total bilirubin within normal institutional limits
- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal (≤ 5.0 X
institutional upper limit of normal permitted if hepatic metastases present)
- Creatinine within 1.5x the ULN institutional limits
- Fasting glucose ≤ 126 mg/dL (7.0 mmol/L)
- HbA1c ≤ 7.0%
- The effects of palbociclib and Gedatolisib (PF-05212384) on the developing human fetus
are unknown. For this reason, women of child-bearing potential and men must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, for the duration of study participation, and 90 days after
discontinuation.
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from acute effects of any prior therapy to baseline or Grade ≤1 except for
Alopecia or AEs not constituting a safety risk in the opinion of the investigator.
- Participants may not be receiving any other study agents concurrently with the study
drugs.
- Participants with symptomatic brain metastases that require active treatment are
excluded.
- Current use or anticipated need for food or medications that are known strong CYP3A4
inhibitors/inducers, including their administration within 7-days prior to the first
Gedatolisib (PF-05212384) or palbocilib dose and during study treatment.
- QTc > 480 msec; history of QT syndrome, Brugada syndrome or known history of QTc
prolongation, or Torsade de Pointes.
- Patients with a history of diabetes.
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
- Pregnant women are excluded from this study because the study agents have the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk of adverse events in nursing infants secondary to treatment of the
mother with the study agents, breastfeeding should be discontinued if the mother is
treated.
- Individuals with a history of other malignancy are ineligible except for the following
circumstances. Individuals with a history of previous malignancies are eligible if
they have been disease-free for at least 2 years and are deemed by the investigator to
be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer
in situ, and basal cell or squamous cell carcinoma of the skin.
- Active and clinically significant bacterial, fungal or viral infection including
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or
acquired immunodeficiency syndrome (AIDS)-related illness.
- Concurrent use or anticipated need for medications that are mainly metabolized by
UGT1A9 including their administration within 7-days prior to the first dose of study
drug.
- Current use or anticipated need for food or medications that are metabolized by
CYP2D6, and of narrow therapeutic index including their administration within 10-days
prior to the first Gedatolisib (PF-05212384) dose and during study treatment.
- Concurrent use of herbal preparations including saw palmetto.
- Current use of drugs known to prolong QT interval.
- Concurrent use of proton pump inhibitors (including, but not limited to,
dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
with palbociclib is prohibited.
