Ulixertinib + Palbociclib for Pancreatic Cancer

Overseen By Catherine Griffin

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Herbal supplements, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Retinal vein occlusion, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I study is designed to establish the safety, maximally tolerated dose (MTD) and recommended phase II dose (RP2D) of the ERK inhibitor ulixertinib (BVD-523) when combined with the CDK4/6 inhibitor palbociclib.

Will I have to stop taking my current medications?

The trial requires participants to stop taking any drugs that strongly affect certain liver enzymes (CYP3A4, CYP1A2, or CYP2D6) at least two weeks before starting the study. You also need to avoid certain herbal preparations and dietary supplements a week before starting. If you're on any of these, you may need to stop or switch medications.

What safety data exists for Palbociclib in combination with other treatments for pancreatic cancer?

A study of Palbociclib combined with nab-paclitaxel in patients with advanced pancreatic cancer assessed its safety, indicating it was part of a clinical evaluation for this condition. ^{1 2 3 4 5}

What makes the drug combination of Ulixertinib and Palbociclib unique for treating pancreatic cancer?

The combination of Ulixertinib and Palbociclib is unique because Ulixertinib is a first-in-class ERK-specific inhibitor that targets a key pathway in pancreatic cancer cells, potentially overcoming resistance seen with other inhibitors, while Palbociclib is a CDK4/6 inhibitor that may enhance the effectiveness of chemotherapy, offering a novel approach to treating this challenging cancer. ^{2 6 7 8 9}

What data supports the effectiveness of the drugs Ulixertinib and Palbociclib for pancreatic cancer?

Research shows that Ulixertinib, an ERK-specific inhibitor, can effectively stop the growth of pancreatic cancer cells in lab studies and works well with other treatments. Palbociclib, when combined with another drug, nab-paclitaxel, has been studied for safety and effectiveness in advanced pancreatic cancer, suggesting potential benefits. ^{2 7 10 11 12}

Research Team

Stergios Moschos, MD

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

Adults with advanced solid tumors, including pancreatic cancer or melanoma that's resistant to standard treatments. Participants must have an ECOG Performance Status of ≤2, a life expectancy ≥12 weeks, and adequate organ function. Women who can bear children need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

My condition did not improve after treatment with a PD1/PD-L1 inhibitor.

I have recovered from the side effects of my last cancer treatment.

My organs are functioning well.

Exclusion Criteria

I am willing to avoid certain fruits for the study.

I cannot or will not stop taking drugs that could affect the study medication.

I have not had major surgery within the last 34 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Establish the safety, maximally tolerated dose (MTD), and recommended phase II dose (RP2D) of ulixertinib combined with palbociclib

5 weeks

Expansion Cohort

Enrollment of patients with metastatic pancreatic cancer and RAS-mutant melanoma after RP2D is defined

Approximately 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to two years

Treatment Details

Interventions

• Palbociclib
• Ulixertinib

Trial Overview The trial is testing the combination of ulixertinib (an ERK inhibitor) with palbociclib (a CDK4/6 inhibitor) to find the safest dose with tolerable side effects for patients with specific types of advanced cancers.

Participant Groups

Group I: Open-label, single arm Phase I Experimental Treatment 2 Interventions

Ulixertinib added to palbociclib

Palbociclib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as Ibrance for:

• HR-positive, HER2-negative locally advanced or metastatic breast cancer

Approved in Canada as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in Japan as Ibrance for:

• HR-positive, HER2-negative advanced or recurrent breast cancer

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

BioMed Valley Discoveries, Inc

Industry Sponsor

Trials

19

Recruited

650+

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

Findings from Research

The combination of palbociclib and nab-paclitaxel showed promising preclinical efficacy against pancreatic ductal adenocarcinoma (PDAC), outperforming gemcitabine plus nab-paclitaxel in three out of four patient-derived xenograft models.

In a clinical trial with 76 patients, the maximum tolerated dose (MTD) was established, but the treatment did not meet the prespecified efficacy threshold of a 12-month survival probability of 65%, achieving only 50% instead.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas. Hidalgo, M., Garcia-Carbonero, R., Lim, KH., et al.[2023]

Ulixertinib, a first-in-class ERK-specific inhibitor, shows effective inhibition of pancreatic ductal adenocarcinoma (PDAC) cell growth in vitro and enhances the effectiveness of gemcitabine, a common chemotherapy drug.

The study also reveals that PDAC cells can activate the PI3K-AKT pathway when treated with ulixertinib, suggesting that combining ulixertinib with PI3K or HER inhibitors could further suppress PDAC growth, providing a strong rationale for future clinical testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models. Jiang, H., Xu, M., Li, L., et al.[2020]

The combination of galunisertib and durvalumab was found to be tolerable with no dose-limiting toxicities, and the recommended dose for further studies was established at 150 mg of galunisertib taken twice daily alongside durvalumab.

While the treatment showed a disease control rate of 25% among 32 patients, clinical activity was limited, suggesting that this combination may be more effective if used earlier in treatment or in patients selected based on specific biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. Melisi, D., Oh, DY., Hollebecque, A., et al.[2021]

In a Phase 1b/2 study involving 156 patients with unresectable pancreatic cancer, the combination of galunisertib and gemcitabine significantly improved overall survival compared to gemcitabine alone.

Potential predictive biomarkers for response to galunisertib plus gemcitabine treatment were identified, including proteins like IP-10, FSH, MIP-1α, and PAI-1, as well as specific miRNAs, suggesting a way to tailor treatments for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Melisi, D., Garcia-Carbonero, R., Macarulla, T., et al.[2022]

A combination of the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib shows a synergistic effect in treating KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), leading to cell-cycle arrest and cell death.

This combination therapy not only remodels the immunosuppressive environment of mesenchymal PDAC but also enhances the infiltration of cytotoxic T cells, making the tumors more responsive to PD-L1 immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. Falcomatà, C., Bärthel, S., Widholz, SA., et al.[2022]

Itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel and gemcitabine, showed an acceptable safety profile and clinical activity in patients with advanced solid tumors, including pancreatic cancer, with a 24% overall response rate across various doses.

The study indicated that while itacitinib was tolerated at lower doses, treatment-related toxicities such as neutropenia and fatigue were common, leading to dose adjustments; however, the study was terminated early due to negative results from a related phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. Beatty, GL., Shahda, S., Beck, T., et al.[2022]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

In a phase II trial involving 50 patients with advanced pancreatic ductal adenocarcinoma (PDAC) and gBRCA/PALB2 mutations, the combination of cisplatin and gemcitabine showed a high response rate of 74.1% and a disease control rate of 100% when combined with veliparib, compared to a 65.2% response rate and 78.3% disease control rate without veliparib.

Despite the addition of veliparib, there was no significant improvement in response rates or overall survival compared to cisplatin and gemcitabine alone, establishing the latter as a standard treatment for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. O'Reilly, EM., Lee, JW., Zalupski, M., et al.[2022]

A study involving 14 patients with pancreatic ductal adenocarcinoma (PDAC) used next-generation sequencing (NGS) to identify mutations and pharmacogenomic biomarkers, confirming known driver mutations like KRAS and TP53.

The analysis revealed that while no changes in therapy were made, the software could predict treatment efficacy and toxicity, suggesting that integrating NGS with evidence-based software could enhance precision medicine approaches for PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer. Malgerud, L., Lindberg, J., Wirta, V., et al.[2018]

In a phase 1b clinical trial involving previously untreated patients with advanced pancreatic ductal adenocarcinoma (PDAC), ibrutinib monotherapy was found to enhance the immune response by increasing activated T cells and monocytes in the blood, indicating its potential to modulate the immune landscape.

However, when ibrutinib was combined with standard chemotherapy (gemcitabine and nab-paclitaxel), these beneficial immune changes were not observed, suggesting that the combination may limit the immunomodulatory effects of ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. Sinha, M., Betts, C., Zhang, L., et al.[2023]

Afatinib, a second-generation EGFR inhibitor, demonstrated growth-inhibitory effects on pancreatic cancer cells and was cytotoxic specifically to cell lines with high levels of EGFR, HER2, and HER3 receptors, regardless of their KRAS mutation status.

The drug increased the sensitivity of certain pancreatic cancer cells to radiation therapy, suggesting a potential for enhanced treatment efficacy when used in combination with ionizing radiation, although these findings need further validation in live models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status. Huguet, F., Fernet, M., Giocanti, N., et al.[2018]

In a phase 2 trial involving 44 patients with locally advanced or metastatic pancreatic cancer, the combination of imatinib mesylate (IM) and gemcitabine (GEM) was found to be tolerated, with common side effects including neutropenia and nausea.

However, the combination treatment did not demonstrate a significant improvement in progression-free survival (PFS) or overall survival (OS) compared to GEM alone, with median PFS of 3.9 months and median OS of 6.3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multi-institutional Phase 2 Study of Imatinib Mesylate and Gemcitabine for First-Line Treatment of Advanced Pancreatic Cancer. Moss, RA., Moore, D., Mulcahy, MF., et al.[2021]

References

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

A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas. [2023]

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

Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. [2022]

6. England pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. [2022]

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

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]

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

Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. [2022]

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

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer. [2018]

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

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. [2023]

11. France pubmed.ncbi.nlm.nih.gov

Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status. [2018]

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

A Multi-institutional Phase 2 Study of Imatinib Mesylate and Gemcitabine for First-Line Treatment of Advanced Pancreatic Cancer. [2021]