Palbociclib + Gedatolisib for Solid Cancers

Recruiting at 2 trial locations

Overseen By Geoffrey Shapiro, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A4 inhibitors, QT prolonging drugs

Disqualifiers: Diabetes, Brain metastases, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

96 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two drugs, Palbociclib (Ibrance) and Gedatolisib (PF-05212384), to determine their effectiveness in treating certain types of cancer. The focus is on cancers potentially linked to a specific change in the PI3K pathway, which can influence cell growth. Individuals with advanced cancers such as squamous cell lung cancer, pancreatic cancer, or head and neck cancer, who may have changes in the PI3K pathway, could be suitable candidates for this trial. Participants should not have undergone recent chemotherapy or radiation and must have managed any other serious health issues. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot use strong CYP3A4 inhibitors/inducers, medications metabolized by UGT1A9 or CYP2D6, drugs that prolong QT interval, or proton pump inhibitors. Check with the study team for specific guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of palbociclib and gedatolisib is generally safe for patients. Earlier studies reported a good safety record for this drug combination, with no severe side effects at the tested doses.

Specifically, a study involving patients with triple-negative breast cancer (TNBC) found the treatment manageable, with patients tolerating the medications well. Another trial combined these drugs with hormone therapy and found similar results, supporting the safety of this combination in various contexts.

These findings suggest that the combination of palbociclib and gedatolisib is safe for people, based on current data. However, individual experiences may differ, so discussing potential risks and benefits with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Palbociclib and Gedatolisib for solid cancers because it offers a unique two-pronged attack on cancer cells. Unlike most standard treatments that target just one aspect of cancer cell growth, Palbociclib inhibits cyclin-dependent kinases 4 and 6 (CDK4/6) to stop cancer cells from dividing, while Gedatolisib targets the PI3K/mTOR pathway, a critical pathway for cancer cell survival and growth. This dual approach aims to effectively halt tumor progression and potentially overcome resistance to current therapies. Additionally, Gedatolisib’s intravenous delivery allows for more controlled dosing, potentially reducing side effects compared to some oral therapies.

What evidence suggests that this trial's treatments could be effective for solid cancers?

Research has shown that the combination of palbociclib and gedatolisib, which participants in this trial will receive, may help treat certain cancers. Palbociclib stops cancer cells from multiplying, while gedatolisib targets a specific part of the cancer cells that aids their growth. Studies have found this combination effective for solid tumors, including some types of breast cancer. Early findings suggest that this duo might work well in cancers with changes in the PI3K pathway, which can help cancer cells survive and spread. Ongoing research aims to confirm these results, but the initial data appears promising. ^{1 2 3 5 6}

Who Is on the Research Team?

Geoffrey I. Shapiro

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with advanced squamous cell lung, pancreatic, head & neck cancers or solid tumors potentially linked to PI3K-pathway changes. They must have acceptable organ function and blood counts, no severe diabetes or heart conditions, not be on certain drugs affecting liver enzymes or the heart's rhythm, and agree to use contraception.

Inclusion Criteria

My cancer has spread, can't be surgically removed, and doesn't respond to standard treatments.

I can take care of myself but might not be able to do heavy physical work.

I have cancer that can be evaluated but not measured for Part I, or cancer that can be measured for Part II.

Exclusion Criteria

I have had chemotherapy or radiotherapy recently.

I am currently using or might need specific medications or special foods.

I do not have brain metastases needing treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Palbociclib orally once daily on Days 1-21 and Gedatolisib intravenously once weekly during 4-week cycles

2 years

Weekly visits for Gedatolisib administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

What Are the Treatments Tested in This Trial?

Interventions

• Gedatolisib
• Palbociclib

Trial Overview The trial is testing a drug combo of Palbociclib and Gedatolisib for treating advanced cancers. It aims to see if these drugs can help patients whose cancer might be affected by specific genetic changes in the PI3K pathway.

How Is the Trial Designed?

Group I: Combination Of Palbociclib and Gedatolisib Experimental Treatment 2 Interventions

* Palbociclib will be administered orally once daily on Days 1-21 for each of the 4-week cycles at a pre-determined dose. * Gedatolisib will be administered intravenously once weekly on the first day for each of the four weeks during the 4-week cycles at a pre-determined dose.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

Gefitinib, a tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), has shown significant efficacy in treating non-small-cell lung cancer (NSCLC), leading to its FDA approval for this refractory disease.

In combination with standard chemotherapy, gefitinib has demonstrated improved response rates in colorectal cancer (75% vs. 55%) and has a mild toxicity profile, making it a promising addition to cancer treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gefitinib (Iressa, ZD1839) and tyrosine kinase inhibitors: the wave of the future in cancer therapy. Penne, K., Bohlin, C., Schneider, S., et al.[2019]

In a Phase 1b study involving 110 patients with advanced solid tumors, gedatolisib combined with cisplatin showed promising clinical activity in triple-negative breast cancer (TNBC), with an overall response rate of 40% in first-line treatment and 33.3% in second/third-line treatment.

The combination therapy was generally well-tolerated, with only 10% of evaluable patients experiencing dose-limiting toxicities, primarily grade 3 oral mucositis, indicating a manageable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer. Curigliano, G., Shapiro, GI., Kristeleit, RS., et al.[2023]

In a study involving 122 patients with advanced solid tumors, the combination of ibrutinib and durvalumab showed an acceptable safety profile, with adverse events consistent with known effects of both drugs.

However, the antitumor activity was limited, with overall response rates of only 2% for pancreatic cancer, 3% for breast cancer, and 0% for non-small cell lung cancer, indicating that this combination may not be effective for these types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors. Hong, D., Rasco, D., Veeder, M., et al.[2021]

Ibrutinib, when combined with standard treatments for advanced renal cell carcinoma (RCC), gastric cancer (GC), and colorectal cancer (CRC), showed overall response rates of 3% for RCC, 21% for GC, and 19% for CRC, indicating limited efficacy in these cancers.

The safety profiles of ibrutinib combined with other drugs were consistent with those of the individual agents, suggesting that the combination therapy is generally safe, but no significant improvements in efficacy were observed compared to historical controls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study. Oh, DY., Maqueda, MA., Quinn, DI., et al.[2023]

Neratinib is an oral pan HER inhibitor that irreversibly blocks the activity of HER2 and other related receptors, showing promise in improving outcomes for patients with HER2-amplified breast cancer, which affects 20% to 25% of cases.

Current clinical trials are evaluating neratinib's safety and efficacy across various cancer types, including breast cancer, with a focus on its use in different treatment settings such as metastatic and adjuvant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Tiwari, SR., Mishra, P., Abraham, J.[2019]

The combination of gedatolisib with carboplatin and paclitaxel showed a promising overall response rate of 65%, particularly high at 80% in patients with clear cell ovarian cancer, indicating preliminary efficacy in treating advanced solid tumors.

The study identified a recommended phase II dose of gedatolisib at 110 mg, with dose-limiting toxicities including neutropenia and mucositis, highlighting the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Dose-Escalation Study of the Dual PI3K-mTORC1/2 Inhibitor Gedatolisib in Combination with Paclitaxel and Carboplatin in Patients with Advanced Solid Tumors. Colombo, I., Genta, S., Martorana, F., et al.[2022]

The maximum tolerated dose of neratinib, an irreversible pan ErbB inhibitor, is 320 mg, with the most common side effect being grade 3 diarrhea, observed in some patients at higher doses.

Neratinib showed preliminary antitumor activity, with a partial response in 32% of breast cancer patients and stable disease in 43% of non-small cell lung cancer patients, indicating its potential effectiveness in treating these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Wong, KK., Fracasso, PM., Bukowski, RM., et al.[2022]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

In a study of 50 patients with advanced EGFR mutation-positive non-small cell lung cancer (NSCLC), both erlotinib and gefitinib showed similar efficacy in terms of objective response rate and disease control rate, with no significant differences found.

The progression-free survival was slightly longer for erlotinib (10.0 months) compared to gefitinib (8.0 months), but overall, the two drugs were comparable in their effectiveness as first-line treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gefitinib versus Erlotinib as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer]. Xie, Y., Liang, J., Su, N.[2018]

Erlotinib and gefitinib are effective targeted therapies for advanced non-small cell lung cancer (NSCLC), specifically inhibiting the epidermal growth factor receptor (EGFR) to improve treatment outcomes.

Recent clinical trials have shown that using these tyrosine kinase inhibitors as first-line treatments can enhance personalized medicine approaches, potentially leading to better clinical outcomes for patients with advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians. Wang, Y., Schmid-Bindert, G., Zhou, C.[2022]

Gefitinib, a targeted therapy for non-small cell lung cancer, has shown a response rate of about 20% in patients who have undergone second-line treatment, with a median survival of 6-8 months based on two large Phase II studies involving pretreated patients.

However, in two large randomized studies assessing gefitinib as a first-line therapy combined with chemotherapy, it did not improve survival or other key outcomes, indicating the need for further research on its role in maintenance therapy or as a standalone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of gefitinib in lung cancer treatment. Giaccone, G.[2018]

Gefitinib is an orally active EGFR-tyrosine kinase inhibitor that effectively blocks cancer cell growth by interfering with signaling pathways, and it has been approved for use in several countries since the early 2000s.

Current clinical trials are exploring gefitinib's efficacy across various solid tumors, including non-small-cell lung cancer and breast cancer, both as a standalone treatment and in combination with other therapies, highlighting its potential to improve cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gefitinib: current and future status in cancer therapy. Herbst, RS., Kies, MS.[2018]

In a phase II study involving patients with recurrent endometrial cancer, gedatolisib showed moderate efficacy with a clinical benefit response rate of 53% in patients with stathmin-low tumors, while PF-04691502 was discontinued early due to unacceptable toxicity, including severe respiratory issues.

Gedatolisib was generally well tolerated, with common side effects including nausea and mucosal inflammation, whereas PF-04691502's daily oral dosing was not well tolerated, indicating that gedatolisib may be a safer option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Del Campo, JM., Birrer, M., Davis, C., et al.[2021]

The combination of Palbociclib and Gedatolisib demonstrated superior anti-proliferative effects in colorectal cancer cell lines compared to the combination of Palbociclib and PD0325901, showing synergy across all tested cell lines.

This combination effectively suppressed S6rp phosphorylation without reactivating AKT, suggesting that monitoring S6rp phosphorylation could serve as a potential biomarker for predicting responsiveness to this treatment in colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of the CDK4/6 inhibitor palbociclib in combination with a PI3K or MEK inhibitor in colorectal cancer. Lee, CL., Cremona, M., Farrelly, A., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03065062

NCT03065062 | Study of the CDK4/6 Inhibitor Palbociclib ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9814742/

A Phase 1B open-label study of gedatolisib (PF-05212384) ... Further assessment of gedatolisib in combination with other therapeutics in breast cancer and other solid tumours is also under consideration, ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00034-2/abstract

Gedatolisib in combination with palbociclib and endocrine ... ... solid tumours and triple-negative breast cancer. Br J Cancer. 2023; 128:30 ... cancer: results from the randomized phase III EMERALD trial. J Clin Oncol ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204524000342

Gedatolisib in combination with palbociclib and endocrine ... Approximately 70% of all breast cancer tumours express the oestrogen receptor, which, on activation, regulates the expression of various genes involved in ...

5. onclive.com onclive.com/view/gedatolisib-based-regimens-may-advance-pik3ca-wild-type-metastatic-breast-cancer-care

Gedatolisib-Based Regimens May Advance PIK3CA Wild- ... Sara A. Hurvitz, MD, FACP, discusses the design of VIKTORIA-1, key efficacy and safety findings, and how these data may influence breast cancer

6. esmoopen.com esmoopen.com/article/S2059-7029(23)00619-1/abstract

204P Phase Ib study of gedatolisib plus palbociclib and ... Here, we report updated baseline characteristics, safety, and efficacy data in treatment naïve patients (pts) treated with gedatolisib + palbo + LET.