PF-07248144 for Breast Cancer

(KAT6 Trial)

Recruiting at 55 trial locations

Overseen By Pfizer CT.gov Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Pfizer

Must be taking: LHRH agonists

Must not be taking: Therapeutic anticoagulants

Disqualifiers: Active malignancy, Major surgery, others

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

Compensation: Varies

Number of Visits: Unknown

320 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a new cancer drug called PF-07248144. It aims to find the best dose and see if it works better alone or with other cancer drugs. The study focuses on cancer patients who may not be responding well to current treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that major surgery, radiation therapy, or systemic anti-cancer therapy should not have occurred within 3 weeks prior to study entry, which might imply a need to pause certain treatments. It's best to discuss your specific medications with the trial team.

What makes the drug PF-07248144 unique for treating breast cancer?

PF-07248144 is a KAT6 inhibitor, which is a novel approach targeting a specific enzyme involved in gene regulation, potentially offering a new mechanism of action compared to existing breast cancer treatments that often target hormone receptors or other pathways. ^{1 2 3 4 5}

What data supports the effectiveness of the drug PF-07248144 for breast cancer?

Research suggests that blocking PPARdelta, a protein that helps cancer cells grow and survive, might be useful in treating breast cancer. Since PF-07248144 is a KAT6 inhibitor, it may work similarly by targeting pathways that help cancer cells thrive, although direct evidence for this specific drug is not provided. ^{6 7 8 9 10}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

Adults with advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC who've exhausted standard treatments. Women must be non-childbearing or agree to induced menopause. Participants need at least one measurable lesion and good organ function but can't join if they have certain GI conditions, recent major surgery, other active cancers (except some skin cancers), are pregnant/breastfeeding, had extensive radiation to the bone marrow, ECG issues, or severe allergies to trial drugs.

Inclusion Criteria

My ER+HER2- breast cancer has worsened after treatment with endocrine therapy and CDK4/6 inhibitor.

I have a tumor that can be measured and hasn't been treated with radiation.

My kidney, liver, and bone marrow are functioning well.

Exclusion Criteria

You have important irregularities in your heart's electrical activity as shown on an ECG.

I have no ongoing severe gut issues or surgeries that could affect medicine absorption.

I have severe fluid buildup in my abdomen that can't be controlled.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of PF-07248144 to determine the maximum tolerable dose (MTD) and select the recommended dose for expansion (RDE).

Up to 29 days

Dose Expansion

Participants receive PF-07248144 at the recommended dose for expansion to evaluate safety, tolerability, and pharmacokinetics.

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PF-07248144

Trial Overview The study is testing PF-07248144's safety and effectiveness alone and in combination with fulvestrant; letrozole + palbociclib; or PF-07220060 + fulvestrant for treating certain advanced cancers. It's an open-label trial where everyone knows what treatment they're getting and aims to understand how the body processes these drugs.

How Is the Trial Designed?

Group I: China Monotherapy Dose Expansion Experimental Treatment 1 Intervention

PF-07248144 Monotherapy Dose Expansion

Group II: 2E Combination Dose Expansion Arm Experimental Treatment 2 Interventions

PF-07248144 with Vepdegestrant Combination Dose Expansion

Group III: 2D Combination Dose Expansion Arm Experimental Treatment 3 Interventions

PF-07248144 with PF-07220060 +Fulvestrant Dose Expansion

Group IV: 2B Combination Dose Expansion Arm Experimental Treatment 2 Interventions

PF-07248144 with Fulvestrant Dose Expansion

Group V: 2A Monotherapy Dose Expansion Arm Experimental Treatment 1 Intervention

PF-07248144 Monotherapy Dose Expansion

Group VI: 1E Combination Dose Escalation Experimental Treatment 2 Interventions

PF-07248144 with Vepdegestrant Combination Dose Escalation

Group VII: 1D Combination Dose Escalation Experimental Treatment 3 Interventions

PF-07248144 with PF-07220060 +Fulvestrant

Group VIII: 1C Combination Dose Escalation Experimental Treatment 3 Interventions

PF-07248144 with Letrozole + Palbociclib Combination Dose Escalation

Group IX: 1B Combination Dose Escalation Experimental Treatment 2 Interventions

PF-07248144 with Fulvestrant Combination Dose Escalation

Group X: 1A Monotherapy Dose Escalation Experimental Treatment 1 Intervention

PF-07248144 Monotherapy Escalation

Who Is Running the Clinical Trial?

Pfizer

Lead 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

GSK3787 is a potent and selective antagonist for the PPARdelta receptor, confirmed through detailed binding studies that showed it covalently binds to a specific site (Cys249) in the receptor's binding pocket.

This compound effectively inhibits the transcriptional activity of PPARdelta and reduces the expression of the CPT1a gene, making it a valuable tool for studying PPARdelta's role in cell biology and pharmacology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist. Shearer, BG., Wiethe, RW., Ashe, A., et al.[2021]

Activation of the PPARdelta receptor by selective agonists significantly stimulates the growth of breast and prostate cancer cell lines, indicating a potential role in cancer progression.

The study suggests that PPARdelta may promote cellular proliferation and angiogenesis through an autocrine loop involving increased expression of growth factors like VEGFalpha, highlighting the therapeutic potential of PPARdelta antagonists in treating these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines. Stephen, RL., Gustafsson, MC., Jarvis, M., et al.[2019]

High levels of PPARδ in breast cancer cells are linked to increased tumor growth and metastasis, suggesting that it plays a critical role in cancer progression.

Targeting PPARδ may offer a new treatment strategy for breast cancer, as it helps cancer cells survive in challenging conditions by reducing oxidative stress and enhancing survival signals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions. Wang, X., Wang, G., Shi, Y., et al.[2020]

In a study using transgenic mice, the expression of PDK1 in mammary tissue was linked to increased tumor formation, especially when combined with the PPARδ agonist GW501516, indicating a potential role in breast cancer progression.

Activation of PPARδ not only accelerated tumor growth but also altered metabolic profiles, suggesting that PDK1 and AKT signaling pathways are involved in enhancing energy metabolism in tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis. Pollock, CB., Yin, Y., Yuan, H., et al.[2022]

Deleting PPARdelta in Apc(Min/+) mice reduced the growth of intestinal adenomas, suggesting that PPARdelta may promote tumor growth in colorectal cancer.

Activation of PPARdelta increased VEGF levels in colon cancer cells, which enhances tumor cell survival through the PI3K-Akt signaling pathway, raising concerns about using PPARdelta agonists in patients at risk for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression. Wang, D., Wang, H., Guo, Y., et al.[2018]

FK228, a histone deacetylase inhibitor, effectively reduces PAK1 kinase activity in breast cancer cells, which is crucial for their estrogen-dependent growth, without altering PAK1 protein levels.

Treatment with FK228 significantly inhibits the growth of both tamoxifen-sensitive and resistant breast cancer cell lines in vivo, indicating its potential as a therapeutic option for patients whose cancers have become resistant to standard estrogen antagonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. Hirokawa, Y., Arnold, M., Nakajima, H., et al.[2021]

The AKAP10 Ile646Val polymorphism is associated with an increased risk of familial breast cancer, with a study of 787 patients showing an odds ratio of 1.25, indicating a significant link between this genetic variant and cancer susceptibility.

Carriers of both the AKAP10 Ile646Val and AKAP13 Lys526Gln variants face an even higher risk of breast cancer (odds ratio of 2.41), suggesting that these genetic factors may influence the effectiveness of PKA-targeted therapies and tamoxifen treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer. Wirtenberger, M., Schmutzhard, J., Hemminki, K., et al.[2013]

PKCiota is identified as a key oncogene in various human cancers, and its overexpression due to gene amplification is linked to tumor growth and invasion, making it a promising target for cancer therapies.

The gold compound ATM has been shown to specifically inhibit the interaction between PKCiota and its effector molecule Par6, demonstrating anti-tumor activity against non-small-cell lung cancer (NSCLC) in both laboratory and animal studies, and is currently undergoing Phase I clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the oncogenic protein kinase Ciota signalling pathway for the treatment of cancer. Fields, AP., Frederick, LA., Regala, RP.[2012]

The study found that the tyrosine kinase inhibitor imatinib inhibits the activity of the ATP-regulated K+ channel (KATP) in pancreatic β-cells, with a half-maximal concentration of about 9.4 μM, indicating a dose-dependent effect.

Imatinib's inhibition of KATP channels is slow and reversible, and the study suggests that this interaction at the ATP-binding site may contribute to some side effects associated with tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib. Fröbom, R., Berglund, E., Aspinwall, CA., et al.[2022]

t-Darpp promotes resistance to trastuzumab in cancer treatment by activating the PKA pathway, which is linked to its ability to sequester regulatory subunits away from the catalytic subunits of PKA, thus enhancing kinase activity.

Phosphorylation of t-Darpp at T39 is essential for its role in activating PKA, suggesting that targeting the t-Darpp-RI interaction could be a potential strategy to overcome drug resistance in cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

t-Darpp stimulates protein kinase A activity by forming a complex with its RI regulatory subunit. Theile, D., Geng, S., Denny, EC., et al.[2018]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. [2021]

7. England pubmed.ncbi.nlm.nih.gov

The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Targeting the oncogenic protein kinase Ciota signalling pathway for the treatment of cancer. [2012]

9. United States pubmed.ncbi.nlm.nih.gov

Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib. [2022]

10. England pubmed.ncbi.nlm.nih.gov

t-Darpp stimulates protein kinase A activity by forming a complex with its RI regulatory subunit. [2018]