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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the safest dose of a new treatment combination for pancreatic cancer. The treatment includes two drugs, ulixertinib (BVD-523) and palbociclib (Ibrance), tested together to evaluate their effectiveness and safety. Individuals with advanced pancreatic cancer who have not responded to other treatments may be suitable candidates for this trial. Participants must have cancer that does not respond to standard care and should be able to swallow pills. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the chance to be among the first to receive this new combination.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research is investigating the combined use of the drugs ulixertinib and palbociclib for treating pancreatic cancer. The goal is to assess the safety of this combination and determine the optimal dose. Previous studies showed that ulixertinib's side effects were as expected, with any serious issues attributed to the cancer itself, not the drug.

Palbociclib, already approved by the FDA for certain breast cancers, has a known safety record. This trial aims to understand how these two drugs interact when used together.

As this study is in its early stages, the primary focus is ensuring the treatment's safety and identifying the correct dose for future research. Participants might experience some side effects, which will be closely monitored. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pancreatic cancer?

Researchers are excited about the combination of Ulixertinib and Palbociclib for pancreatic cancer because it targets cancer cells in a novel way. Unlike traditional treatments that mainly focus on chemotherapy, this combination works by inhibiting specific proteins involved in cancer cell growth. Ulixertinib targets the ERK pathway, while Palbociclib inhibits CDK4/6, both of which are crucial for cancer cell proliferation. This dual approach could potentially block cancer progression more effectively than existing therapies, offering new hope for patients with this challenging condition.

What evidence suggests that ulixertinib combined with palbociclib might be an effective treatment for pancreatic cancer?

Research shows that ulixertinib alone modestly slows tumor growth, while palbociclib alone has limited impact. In this trial, researchers are combining ulixertinib with palbociclib in a single treatment arm to evaluate their combined effect. Early studies suggest that using both drugs together could slow cancer growth more effectively than using either one alone. Ulixertinib targets a protein called ERK, which aids cancer cell growth, while palbociclib blocks CDK4/6, another pathway for cancer cell multiplication. The aim is that attacking cancer from two different angles will enhance treatment effectiveness. ^{1 2 3 6 7}

Who Is on the Research Team?

Stergios Moschos, MD

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03454035

Study Details | NCT03454035 | Ulixertinib/Palbociclib in ... 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 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.e15101

Updated clinical outcomes from ULI-EAP-100, an ... Results: As of February 1st, 2022, 48 patients (pts) across 17 sites have been treated with ulixertinib under ULI-EAP-100 including pts with ...

3. aacrjournals.org aacrjournals.org/cancerres/article/82/12_Supplement/1057/699976/Abstract-1057-Significant-efficacy-demonstrated

Abstract 1057: Significant efficacy demonstrated with the ... Palbociclib monotherapy across all models showed limited tumor growth inhibition (TGI) while ulixertinib monotherapy demonstrated modest TGI ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3103

A phase Ib trial of ERK inhibition with ulixertinib combined ... This phase 1b study evaluated the safety, pharmacokinetics, and early clinical efficacy of ulixertinib when combined with the oral CDK4/6 inhibitor palbociclib ...

5. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03454035/

Clinical Trial: NCT03454035 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 ( ...

6. asco.org asco.org/abstracts-presentations/ABSTRACT331965

A phase Ib trial of ERK inhibition with ulixertinib combined ... A phase Ib trial of ERK inhibition with ulixertinib combined with palbociclib in patients (Pts) with advanced solid tumors. ; 2, 450, 100 ; 3, 600, 75 ; 2A, 450

7. ascopubs.org ascopubs.org/doi/10.1200/EDBK_397082

Advancements in Systemic Therapy for Pancreatic Cancer Eight patients (21%) had a confirmed partial response, and 24 (63%) had stable disease as their best response. The median PFS in the trial was ...