Molecularly Tailored Therapy in Advanced Pancreatic Cancer

TAILOR-PANC (DPCG-02) is an investigator-initiated, multicenter, randomized phase 2 trial evaluating whether molecularly tailored second-line therapy improves outcomes compared with standard-of-care treatment in patients with advanced pancreatic cancer.

Although most pancreatic cancers harbor KRAS mutations, a smaller proportion contain potentially actionable molecular alterations, including selected mutations, gene fusions, amplifications, or biomarkers such as mismatch repair deficiency. Some of these alterations can be targeted by medicines that are already available in Denmark, although the medicines may have been developed or approved primarily for other cancer types. Observational studies suggest that patients with pancreatic cancer who receive treatment matched to an actionable alteration may have better outcomes than patients who receive non-matched treatment. However, this strategy has not been adequately evaluated in a randomized setting.

Molecular profiling is performed before study allocation using tumor tissue and/or blood. Whole-genome sequencing is preferred, but targeted next-generation sequencing or whole-exome sequencing may be used when whole-genome sequencing is unavailable. The results are summarized in a personalized molecular report. A national multidisciplinary molecular tumor board, including pancreatic cancer oncologists, molecular biologists, pathologists, and computational biologists, reviews the molecular findings and assesses whether an alteration is clinically actionable. A molecular alteration is considered actionable when it can be matched to a specific anticancer treatment supported by clinical evidence and the treatment is available and reimbursed in Denmark.

Participants whose cancers harbor an actionable, reimbursed molecular alteration are randomized in a 1:1 ratio to:

Arm 1: molecularly tailored therapy selected according to the recommendation of the national molecular tumor board; or Arm 2: standard second-line therapy according to Danish clinical guidelines.

Because the molecular alteration determines the matched treatment, participants assigned to Arm 1 may receive different targeted treatments. The relevant drug-specific requirements, safety monitoring, dose modifications, and discontinuation criteria will apply to each treatment.

Participants whose cancers do not harbor an actionable, reimbursed molecular alteration are assigned to Arm 3, a non-randomized observational cohort receiving standard-of-care therapy according to Danish guidelines. Data from this cohort will support exploratory comparisons and provide information about outcomes among genomically profiled patients without an available matched treatment. Comparisons involving Arm 3 will be interpreted as non-randomized because molecular characteristics and other prognostic factors may differ between the groups.

The primary randomized comparison is progression-free survival between Arms 1 and 2. Approximately 68 participants with actionable alterations are required for randomization, with approximately 65 progression-free survival events planned for the primary analysis. The study is designed to provide approximately 80% power at a two-sided significance level of 0.05 to detect a hazard ratio of 0.50. This corresponds to the design assumption of an increase in median progression-free survival from 3 months with standard therapy to 6 months with molecularly tailored therapy. These values are statistical assumptions and do not represent guaranteed treatment outcomes.

Because actionable alterations are expected in only approximately 5%-10% of patients with pancreatic cancer, up to 1,200 genomically profiled participants may be enrolled to identify the required number for the randomized comparison. Recruitment is expected to take approximately 4 years, with approximately 1 additional year of minimum follow-up for the primary analysis.

The study will also characterize overall survival, tumor response, duration of response, safety, and patient-reported quality of life. Optional translational research will be conducted through the BIOPAC project under separate consent. Blood and available tumor samples may be used to explore molecular and circulating biomarkers associated with treatment response, resistance, and toxicity. Clinical and genomic data may also be used in exploratory artificial intelligence and machine-learning analyses intended to develop predictive models and identify potential therapeutic targets. These biomarker and computational analyses are exploratory and are not used as validated clinical tests within this study.

• Arm 1: Molecularly Tailored Therapy (Drug): Axitinib Crizotinib Dabrafenib Trametinib Erlotinib Larotrectinib Olaparib Pembrolizumab Pemigatinib Pertuzumab and trastuzumab (Phesgo9 Selpercatinib Vismodegib
• Arms 2: Standard-of-Care Therapy (Drug): Gemcitabine Nab-paclitaxel 5-Fluorouracil; 5-FU Calcium folinate Oxaliplatin Irinotecan Capecitabine
• Arm 3: Standard-of-Care Observational Cohort (Drug): Gemcitabine Nab-paclitaxel 5-Fluorouracil; 5-FU Calcium folinate Oxaliplatin Irinotecan Capecitabine

Primary outcomes

• Progression-Free Survival in Randomized Participants [1 year]: Progression-free survival is defined as the time from the first dose of study treatment to investigator-assessed objective disease progression according to RECIST version 1.1 or death from any cause in the absence of documented progression, whichever occurs first. Participants without progression or death at the analysis will be censored at their latest evaluable RECIST assessment. The primary comparison is between molecularly tailored therapy (Arm 1) and standard-of-care therapy (Arm 2).

Secondary outcomes

• Overall Survival in Randomized Participants [1 year]: Overall survival is defined as the time from the first dose of study treatment until death from any cause. Participants not known to have died at the time of analysis will be censored on the last date they were known to be alive. Overall survival will be compared between Arm 1 and Arm 2.
• Overall Survival Rate at 6 Months [6 months]: The proportion of randomized participants alive 6 months after the first dose of study treatment, estimated using the Kaplan-Meier method.
• Overall Survival Rate at 12 Months [12 months]: The proportion of randomized participants alive 12 months after the first dose of study treatment, estimated using the Kaplan-Meier method.
• Confirmed Objective Response Rate [1 year]: The percentage of randomized participants with a confirmed complete response or partial response according to investigator assessment using RECIST version 1.1. A response must be confirmed by repeat imaging performed at least 4 weeks after the response was first observed, with no evidence of progression between assessments.
• Disease Control Rate at 4, 6, and 12 Months [12 months]: The percentage of randomized participants with a best overall response of complete or partial response within the specified period or stable disease maintained for the corresponding minimum period, according to investigator assessment using RECIST version 1.1. Disease control will be assessed at 4, 6, and 12 months after treatment initiation.
• Duration of Response [1 year]: Among randomized participants with a documented complete or partial response, duration of response is defined as the time from the first documented response until objective disease progression according to RECIST version 1.1 or death from any cause in the absence of documented progression. Participants without progression or death following a response will be censored according to the progression-free survival censoring rules.
• Progression-Free Survival After Subsequent Therapy [1 year]: Progression-free survival 2 is defined for randomized participants receiving subsequent anticancer treatment after first disease progression as the time from the first dose of randomized study treatment until the second objective disease progression or death from any cause in the absence of second progression, whichever occurs first.
• Incidence and Severity of Treatment-Related Adverse Events [1 year]: The number and percentage of randomized participants experiencing adverse events, including serious adverse events, considered causally related to study treatment. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Safety assessments also include deaths, laboratory findings, vital signs, electrocardiograms, and treatment exposure.
• Change From Baseline in EORTC QLQ-C30 Scores [1 year]: Adjusted mean change from baseline in the EORTC QLQ-C30 global health status/quality-of-life score and functional and symptom scales will be compared between randomized treatment arms. Scores will be calculated according to the EORTC scoring manual. Higher global health and functional scale scores indicate better functioning, whereas higher symptom scale scores indicate greater symptom burden.

Other outcomes

• Overall Survival Across Molecular and Treatment Cohorts [1 year]: Overall survival will be explored by comparing molecularly tailored therapy in Arm 1 with standard-of-care therapy in Arm 3 and standard-of-care therapy in Arm 2 with standard-of-care therapy in Arm 3. Because Arm 3 includes participants without an actionable reimbursed molecular alteration and is not randomized, these comparisons are exploratory and may be affected by differences in molecular and clinical characteristics.
• Objective Response Rate Across Molecular and Treatment Cohorts [1 year]: Objective response rate will be explored by comparing Arm 1 with Arm 3 and Arm 2 with Arm 3. Objective response is defined as complete or partial response based on available investigator-assessed tumor evaluations. Comparisons involving Arm 3 are non-randomized and exploratory.
• Correlations of Tumor and Blood Biomarkers With Clinical Outcomes [Up to 5 years]: Exploratory biomarkers measured in available tumor tissue and peripheral blood before and during treatment will be summarized and evaluated for associations with objective response, best overall response, duration of response, disease control, progression-free survival, safety, and other clinical outcomes. Analyses will include baseline biomarker values and absolute or percentage changes from baseline. Biomarker sampling is optional through the BIOPAC project and requires separate consent.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adult patients (aged 18 and over)
* PC confirmed by cytology or histology
* Written informed consent before any specific study procedures
* Available personalized report communicating the molecular testing results and detailed treatment options
* Participants must have received and progressed during or after 1 line of systemic chemotherapy in the advanced setting (gemcitabine or 5-FU based regimens) or within one year of the adjuvant/neoadjuvant treatment

Notes:

* In general, discontinuation of 1 drug in a multi-drug regimen and continuation of other drug(s), is considered part of the same line of treatment. Restarting the same regimen after a drug holiday or maintenance chemotherapy can also be considered part of the same line of treatment
* Switching from IV (5-FU) to an oral formulation (capecitabine) of the same drug is also considered part of the same line of treatment
* Minimum time from first systemic therapy for advanced PC to progression should be at least 2 months

  * ECOG Performance Status (PS) 0-2
  * Participants must have normal organ and marrow function as defined below:
* Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
* Platelet count ≥ 75 x 10⁹/L
* Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
* AST/ALT ≤ 5 x ULN
* Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 50 mL/min (using the Cockcroft-Gault formula)

  * Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated in the protocol
  * Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year

Exclusion Criteria:

* Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
* Allergies and Adverse Drug Reaction

  * History of allergy to study drug components
  * History of severe hypersensitivity reaction to any monoclonal antibody (applicable for participants to receive a monoclonal antibody in the trial)
* WOCBP who are pregnant or breastfeeding

• Inna Markovna Chen, MD, Principal investigator, Herlev Sygehus