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Trial ID: NCT05172258
A Phase 2 Study of Ipatasertib in Combination With Pembrolizumab for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck
- Patients must have histologically or cytologically confirmed recurrent or metastatic
head and neck squamous cell carcinoma (HNSCC) that is considered incurable.
- Patients 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 for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >=10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam.
- Primary tumor locations of oral cavity, oropharynx, hypopharynx, and larynx are
allowed. Participants may not have a primary tumor site of nasopharynx.
- Patients with oropharyngeal cancer must have known human papillomavirus (HPV) status
defined by human papillomavirus type 16 (p16) testing.
- Patients should not have had prior systemic therapy administered in the recurrent or
metastatic setting. Systemic therapy which was given as part of multimodal treatment
for locally advanced disease is allowed.
- Patients must be able to provide an archival tissue specimen.
- Tumor tissue must have a documented combined positive score (CPS) of >= 1 for PD-L1.
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of ipatasertib in combination with pembrolizumab in patients < 18 years of
age, children are excluded from this study.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >=
- Absolute neutrophil count >= 1,000/mcL.
- Platelets >= 100,000/mcL.
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]
=< 3 x institutional ULN.
- Creatinine =< 1.5 x institutional ULN.
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 (using the Cockcroft-Gault
- Human immunodeficiency virus (HIV) infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial.
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated.
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load.
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression.
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial.
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better.
- Patients must be able to swallow orally administered medication whole.
- For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraceptive methods with a failure rate of <
1% per year during the treatment period, for 5 months after the last dose of
pembrolizumab and 28 days after the last dose of ipatasertib, and agreement to refrain
from donating eggs during this same period.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, agreement to refrain from donating sperm during the treatment
period, and for 5 months after the last dose of pembrolizumab and 28 days after the
last dose of ipatasertib.
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
- Prior treatment with a checkpoint inhibitor given for relapsed or metastatic disease.
Prior treatment with a checkpoint inhibitor for locally advanced disease as part
multidisciplinary treatment is allowed.
- History of malabsorption syndrome or other condition that would interfere with enteral
absorption or result in the inability or unwillingness to swallow pills.
- Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
The use of physiologic doses of corticosteroids may be approved after consultation
with the study principal investigator (PI).
- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
- Type 1 or Type 2 diabetes mellitus requiring insulin at study entry are ineligible.
- Patients who are on a stable dose of oral diabetes medication >= 4 weeks prior to
initiation of study treatment may be eligible for enrollment. Patients must meet
the laboratory eligibility criteria for fasting blood glucose and hemoglobin A1c.
- Fasting glucose =< 150 mg/dL (8.3 mmol/L) and hemoglobin A1c =< 7.5% (58
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study.
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1). Note: Patients with grade =< 2 neuropathy
or grade =< 2 alopecia are an exception to this criterion and may qualify for the
study. Note: If patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
- Patients who are receiving any other investigational agents.
- Patients with known active CNS metastases and/or carcinomatous meningitis. Patients
with previously treated brain metastases may participate provided they are
radiologically stable, i.e., without evidence of progression for at least 4 weeks by
repeat imaging (note that the repeat imaging should be performed during study
screening), clinically stable and without requirement of steroid treatment for at
least 14 days prior to first dose of study treatment.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ipatasertib or hypersensitivity (grade >= 3) to pembrolizumab and/or
any of the components of the solution for injection.
- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
drug-elimination half-lives, whichever is longer, prior to initiation of study drug is
prohibited. Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently-updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
- Patients with uncontrolled intercurrent illness (including but not limited to
interstitial lung disease or active, non-infectious pneumonitis) or a history of
(non-infectious) pneumonitis that required steroids.
- Patients with psychiatric illness/social situations that would limit compliance with
- Patients who are pregnant or breastfeeding, or are expecting to conceive or father
children within the projected duration of the study, starting with the screening visit
through 5 months after the last dose of study treatment. A WOCBP who has a positive
urine pregnancy test (e.g., within 72 hours) prior to treatment will be excluded from
the study. If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required. Pregnant women are excluded from this study because
pembrolizumab is a monoclonal antibody agent and ipatasertib is an oral AKT inhibitor
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with pembrolizumab and ipatasertib, breastfeeding should be
discontinued if the mother is treated with pembrolizumab or ipatasertib. Due to the
potential risks, WOCBPs 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 for 5 months after the last dose of pembrolizumab and 28 days
after the last dose of ipatasertib. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.
- Patients with grade >= 2 uncontrolled or untreated hypercholesterolemia or
hypertriglyceridemia are excluded.
- Patient has a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer)
that has undergone potentially curative therapy.
- History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
colitis) or active bowel inflammation (e.g., diverticulitis).
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic
infections (pneumocystis pneumonia or cytomegalovirus pneumonia).
- Known clinically significant history of liver disease consistent with Child Pugh Class
B or C, including active viral or other hepatitis (e.g., positive for hepatitis B
surface antigen [HbsAg] or hepatitis C virus [HCV] antibody at screening), current
drug or alcohol abuse, or cirrhosis.
procedure: Biospecimen Collection
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