Combining Palbociclib and Gedatolisib for Advanced Solid Tumors

Phase I Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors

This study is testing a new combination of two cancer drugs, Palbociclib and Gedatolisib, to see if it can help people with advanced solid tumors that haven't responded to other treatments.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 96 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Dana-Farber Cancer Institute (other)
• Drugs / interventions: chemotherapy
• Locations: 3 sites (Boston, Massachusetts and 2 other locations)
• Trial ID: NCT03065062 on ClinicalTrials.gov

What this trial studies

This clinical trial is an open-label Phase I study evaluating the safety and appropriate dosing of the combination of Palbociclib and Gedatolisib in patients with advanced solid tumors, including squamous cell lung, pancreatic, and head & neck cancers. The study aims to determine if this drug combination can effectively shrink or halt the growth of cancer by targeting specific pathways involved in cell growth and survival. Participants must have tumors that are either metastatic or unresectable and resistant to standard therapies. The trial will assess the tolerability of the treatment and its potential effectiveness in patients with specific genetic markers related to the PI3K pathway.

Who should consider this trial

Good fit: Ideal candidates include patients with advanced squamous cell lung cancer, pancreatic cancer, head & neck cancer, or other solid tumors with suspected PI3K-pathway dependence.

Not a fit: Patients with early-stage cancers or those who have not exhausted standard treatment options may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced cancers that are resistant to existing therapies.

How similar studies have performed: Other studies have shown promise with similar drug combinations targeting the PI3K pathway, but this specific combination is novel.

Eligibility criteria

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.

Where this trial is running

Boston, Massachusetts and 2 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (NOT_YET_RECRUITING)
• Beth Israel Deaconess Medical Center — Boston, Massachusetts, United States (NOT_YET_RECRUITING)
• Dana Farber Cancer Institute — Boston, Massachusetts, United States (RECRUITING)

Study contacts

• Principal investigator: Geoffrey Shapiro, MD — Dana-Farber Cancer Institute
• Study coordinator: Geoffrey Shapiro, MD

Conditions: Lung Cancer Squamous Cell, Solid Tumors, Head & Neck Cancer, Pancreatic Cancer, Neoplasms, Endometrial Cancer