Pancreatic Ductal Adenocarcinoma, Pancreatic Cancer, Resectable Pancreatic Ductal Adenocarcinoma
Conditions
Keywords
Pancreatic Ductal Adenocarcinoma, Pancreatic Cancer, Resectable Pancreatic Ductal Adenocarcinoma, daraxonrasib, RMC-6236, resectable PDAC, surgery, adjuvant chemotherapy, radiation therapy, targeted therapy, genetic studies
Brief summary
This Phase 1 interventional treatment study is evaluating oral daraxonrasib in participants with resectable pancreatic ductal adenocarcinoma. The study includes pre-surgery daraxonrasib treatment, surgery, adjuvant chemotherapy with or without radiation, optional adjuvant daraxonrasib, and follow-up. The protocol also includes research blood, stool, tissue, and de-identified data collection for correlative and future research.
Detailed description
This is a DF/HCC PI-sponsored Phase 1 interventional treatment trial in resectable pancreatic ductal adenocarcinoma. Participants are screened before starting treatment and then assigned to one of two protocol-defined cohorts that differ in the duration of neoadjuvant daraxonrasib before surgery. Study treatment includes oral daraxonrasib once daily during 28-day cycles before surgery, followed by surgical resection, adjuvant chemotherapy with or without radiation per institutional standard and physician discretion, and optional adjuvant daraxonrasib for up to 32 cycles (24 months) after completion of adjuvant therapy. The study includes safety monitoring, tumor assessments, laboratory testing, collection of archival tumor tissue, research blood and stool, and sharing of de-identified data and biospecimens with outside collaborators for analysis and future research. Planned accrual is 30 participants over 24 months, with post-treatment follow-up at least every 6 months for up to 5 years.
Interventions
DRUGDaraxonrasib
Oral study drug taken once daily in 28-day cycles at a predetermined dose before surgery, and optionally again in the adjuvant setting after completion of adjuvant therapy.
PROCEDURESurgical Resection
Protocol-planned surgery performed after neoadjuvant daraxonrasib treatment and surgical planning.
DRUGAdjuvant Chemotherapy
Post-surgery chemotherapy administered per institutional standard and investigator/physician discretion.
RADIATIONAdjuvant Radiation Therapy
Post-surgery radiation therapy may be given with adjuvant chemotherapy according to institutional standard and investigator/physician discretion.
Sponsors
Dana-Farber Cancer Institute
Revolution Medicines, Inc.
The Mark Foundation for Cancer Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The clinical, radiographic, and pathologic evidence support a diagnosis of pancreatic adenocarcinoma, with histology confirmatory for adenocarcinoma, adenosquamous carcinoma, or poorly differentiated carcinoma. * Subjects must be determined to meet the criteria for resectable pancreatic cancer based on National Comprehensive Cancer Network (NCCN) criteria at initial diagnosis (Table 2). Patients with borderline resectable, locally advanced, or metastatic disease are not eligible for this trial. Resectability status * Resectable * Borderline resectable * Locally advanced Arterial * No arterial tumor contact (celiac axis (CA), superior mesenteric artery (SMA), or common hepatic artery (CHA)) * Pancreatic head/uncinate process: * Solid tumor contact with CHA without extension to CA or hepatic artery bifurcation allowing for safe and complete resection and reconstruction. * Solid tumor contact with the SMA of ≤180°. * Solid tumor contact with variant arterial anatomy (eg, accessory right hepatic artery, replaced right hepatic artery, replaced CHA, and the origin of replaced or accessory artery) and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning. Pancreatic body/tail: * Solid tumor contact with the CA of ≤180°. Head/uncinate process: * Solid tumor contact \>180° with the SMA or CA. Pancreatic body/tail: * Solid tumor contact of \>180° with the SMA or CA. * Solid tumor contact with the CA and aortic involvement. Venous -No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) OR ≤ 180° of contact without vein contour irregularity. Solid tumor contact with the SMV or PV of \>180°, contact of ≤180° with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement allowing for safe and complete resection and vein reconstruction. Solid tumor contact with the inferior vena cava (IVC). Not currently amenable to resection and primary reconstruction due to complete occlusion of SMV/PV \*NCCN guideline definition of resectability status * Prospective determination of RAS mutation status is not required * Participants must be ≥ 18 years old * Participants must have an ECOG performance status of 0 or 1 Participants must have adequate organ and marrow function as defined as: * Absolute neutrophil count ≥1,500/mcL * Platelets ≥100,000/mcL * Hemoglobin ≥ 8 g/dL * Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) or \<2 x ULN in patients with Gilbert syndrome * AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN * Creatinine Calculated estimated glomerular filtration rate ≥60 mL/min * Coagulation function PT/INR/PTT \<1.5 x ULN, or ≤ 2 x ULN for those on anticoagulation * Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 9 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. * Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy. * Ability to swallow oral medications and willing to keep daily adherence record. * Ability to understand and the willingness to sign a written informed consent document * Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Presence of metastatic disease * Requirement of pre-operative or neoadjuvant radiation therapy to primary pancreatic tumor as determined by multi-disciplinary tumor board. * Tumors with the following histologic features in addition to an adenocarcinoma component are excluded: neuroendocrine, undifferentiated with osteoclast like giant cells, acinar, hepatoid, medullary carcinomas. * Known BRAF activating mutation or gene rearrangement that is suggestive of resistance to daraxonrasib * Prior treatment with MAPK targeted therapy including pan-RAS, pan-KRAS, KRAS mutant allele specific, BRAF, MEK, or ERK inhibitors. * Treatment with any investigational agents within the last 14 days or 5 half-lives, whichever is shorter, from C1D1 of this trial drug. No prior treatment for pancreatic cancer is allowed. * Has a left ventricular ejection fraction \<50% within 4 weeks, symptomatic heart failure within 4 weeks, acute coronary syndrome within 6 months or medically uncontrolled hypertension (\>160 mmHg systolic blood pressure or \>100 diastolic blood pressure) based on average of 3 readings. * Prolonged QTc interval \>470ms, averaged from 3 electrocardiograms (EKGs). * History of or active interstitial lung disease, pneumonitis, pulmonary fibrosis which required steroid treatment within 6 months. * Known or suspected gastrointestinal disorder which may hinder ability to take PO drug or hinder absorption * Requires treatment with systemic cyclosporine A or derivative * Has had consumption within the last 14 days or 5 half-lives, whichever is shorter, from C1D1 of this trial drug or requires ongoing consumption of P-gp or CYP3A inducers or inhibitor (See APPENDIX B) * Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study. * Has a history of other cancers diagnosed or treated within last 3 years. Clinically insignificant cancers which require no significant treatment or tumors treated with definitive intent and with low risk of recurrence are not excluded. Discussion with sponsor investigator is encouraged. * Subject is unable or unwilling to participate in a study related procedure. * Has an active serious infection requiring systemic therapy * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Successful Receipt of Surgery Rate | After 6- or 12-weeks of neoadjuvant therapy | Proportion of participants who complete neoadjuvant darazonrasib therapy and then attempt surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Response Rate | After 6- or 12-weeks of neoadjuvant therapy | Proportion of participants who achieve pathologic response defined as tumor regression of grades 0 or 1 in all participants who underwent resection based on evaluation of the resected pancreatic tumor specimen by an experienced pathologist as reported according to College of American Pathologist guidelines (2012). |
| Grade 3-4 Adverse Event Rate | After 6- or 12-weeks of neoadjuvant therapy | Proportion of participants who experience a grade 3 or 4 adverse event on neoadjuvant darazonrasib therapy as measured by CTCAE version 5. |
| R0 Resection Rate | After 6- or 12-weeks of neoadjuvant therapy | Proportion of participants who undergo surgery after completing neoadjuvant darazonrasib therapy and achieve negative margin (R0) resection status. |
| Objective Response Rate (ORR) | After 6- or 12-weeks of neoadjuvant therapy | ORR is defined as the proportion of participants achieving complete response (CR) or partial response (PR) on neoadjuvant darazonrasib therapy. Per RECIST 1.1 criteria for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
| Disease Control Rate (DCR) | After 6- or 12-weeks of neoadjuvant therapy | DCR is defined as the proportion of participants achieving CR, PR or stable disease (SD) on neoadjuvant darazonrasib therapy. Per RECIST 1.1 criteria: SD is not achieving PR or experiencing disease progression (PD). PD per RECIST 1.1 for target lesions is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
Countries
United States
Contacts
CONTACTBrandon Huffman, MD
PRINCIPAL_INVESTIGATORBrandon Huffman, MD
Dana-Farber Cancer Institute
Outcome results
None listed