Ulixertinib + Palbociclib for Pancreatic Cancer
Recruiting in Palo Alto (17 mi)
Overseen ByStergios Moschos, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: UNC Lineberger Comprehensive Cancer Center
Must not be taking: Herbal supplements, CYP3A4 inhibitors
Disqualifiers: Pregnancy, Retinal vein occlusion, others
No Placebo Group
Breakthrough Therapy
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 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.
12345What 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.
16789What 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.
12101112Eligibility 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.
+14 more
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.
+11 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Open-label, single arm Phase IExperimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Lineberger Comprehensive Cancer CenterChapel Hill, NC
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Who Is Running the Clinical Trial?
UNC Lineberger Comprehensive Cancer CenterLead Sponsor
BioMed Valley Discoveries, IncIndustry Sponsor
PfizerIndustry Sponsor
References
A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas. [2023]To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).
Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models. [2020]Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K-AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients. Mol Cancer Ther; 17(10); 2144-55. ©2018 AACR.
Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. [2021]We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens.
TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. [2022]Galunisertib, the first small molecule transforming growth factor beta (TGFβ) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking.
Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. [2022]KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.
A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. [2022]Label="LESSONS LEARNED">Itacitinib in combination with nab-paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents.
Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation.
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]Label="PURPOSE">Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline BRCA1/2 or PALB2 (gBRCA/PALB2+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in gBRCA/PALB2+ PDAC.
Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer. [2018]Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off-label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software-analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.
Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. [2023]In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.
Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status. [2018]Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has shown modest activity in most patients.
A Multi-institutional Phase 2 Study of Imatinib Mesylate and Gemcitabine for First-Line Treatment of Advanced Pancreatic Cancer. [2021]The pancreatic tumor microenvironment is rich in receptors for platelet-derived growth factor (PDGFRs). Imatinib mesylate (IM) inhibits PDGFRs and decreases tumor interstitial fluid pressure, potentially improving drug access. These data and promising results in a phase 1 trial formed the rationale for a phase 2 trial combining IM and gemcitabine (GEM) in pancreatic cancer.