J1130, Phase 1b/2 Safety and Feasibility of Gemcitabine and Nab-Paclitaxel in combination with LDE-225 as Neoadjuvant Therapy in Patients with Borderline Resectable Pancreatic Adenocarcinoma.
Ana De jesus-acosta
Here we propose a phase 1b/2 safety and feasibility study to evaluate whether or not combining these agents in a neoadjuvant setting is safe and improves the resection rate in patients with BR PDA. The pre-operative agents will include the cytotoxic agent gemcitabine with the Hh inhibitor LDE-225. Correlative aims to elucidate how Hh inhibitors disrupt stromal-tumor signaling, provide clinical benefit, and affect drug delivery changes will be explored. We hypothesize that adding Hh inhibitors to cytotoxic agents is safe and will result in increased resection rates. Due to the lack of prospective controlled studies to estimate the true resection rate in patients with BR pancreatic cancer, stromal desmoplasia scores and intratumoral drug concentrations we will conduct a pilot safety and feasibility study.
Eligibility Criteria -Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas. Patients who have not undergone biopsy but have highly suspected adenocarcinoma of the pancreas with borderline resectable features on imaging study may also be eligible for study and undergo the pretreatment biopsy as per protocol. The biopsy must confirm adenocarcinoma of the pancreas to continue on study. Biopsy is required within 14 days of starting therapy. -Patients must have borderline resectable pancreatic adenocarcinoma defined by one of the following criteria: (1) Tumor associated deformity of the superior mesenteric vein (SMV) or portal vein (PV) (2) Abutment of the SMV or PV less than 1800 (3) Short-segment occlusion of the SMV or PV amenable to resection and venous reconstruction (4) Short-segment involvement of the hepatic artery or its branches amenable to resection and reconstruction or (5) Abutment of the superior mesenteric artery (SMA) less than 1800 -Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than 20 mm with conventional techniques or as greater than 10 mm with spiral CT scan. See Section 11 for the evaluation of measurable disease. -Patient must have received no previous radiotherapy, surgery, chemotherapy or investigational drug therapy. -Age greater than 18 years. Because no dosing or adverse event data are currently available on the use of LDE225 in combination with gemcitabine in patients less than 18 years of age, children are excluded from this study but will be eligible for future pediatric phase 2 combination trials. -Life expectancy of greater than 1 month. -ECOG performance status less than 1 (Karnofsky greater than 70%; see Appendix A). -Patients must have adequate organ and marrow function as defined below: -leukocytes greater than 3,000/mcL -absolute neutrophil count greater than 1,500/mcL -platelets greater than 100,000/mcL -total bilirubin less than 1.5 ULN -AST(SGOT)/ALT(SGPT) less than 2.5 X institutional upper limit of normal, unless liver metastases are clearly present, then less than 5X ULN is allowed liver -creatinine within normal institutional limits OR -creatinine clearanceCreatinine clearance greater than 50 mL/min/1.73 m2 for patients with serum creatinine less than 2 mg/mL -Patients should be asymptomatic for jaundice and ascites prior to Day 1. Pain symptoms should be stable. -The effects of LDE225 on the developing human fetus are unknown. For this reason and because other Hh signal pathway inhibitors are known to be teratogenic, women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) for the duration of study participation, and for at least 12 months post-treatment. For appropriate methods of contraception considered acceptable see Appendix B. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Pregnancy Testing. Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of LDE225 (serum or urine). A pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study. A positive urine test must be confirmed by a serum pregnancy test. Prior to dispensing LDE225, the investigator must confirm and document the patientâ??s use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient understands of the possible teratogenic potential of LDE225. Women of childbearing potential are defined as follows: â?¢Patients with regular menses â?¢Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding â?¢Women who have had a tubal ligation Women are considered not to be of childbearing potential for the following reasons: â?¢The patient has undergone hysterectomy and/or bilateral oophorectomy. â?¢The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman greater than 45 years old. -For sexually active males, use of barrier form of contraception, even if they have had a vasectomy, during the study and for 3 months after stopping LDE225 is required. Males should not donate sperm during treatment or up to three months after last dose. -All patients should agree not to donate blood products for 12 months after stopping LDE225 -Ability to understand and the willingness to sign a written informed consent document. -Patient is willing to have two biopsies while on treatment for correlative studies. Exclusion Criteria -Patients who have had chemotherapy or radiotherapy for pancreatic adenocarcinoma. -Patients may not be receiving any other investigational agents. -Patient has known metastatic disease. -History of allergic reactions attributed to compounds of similar chemical or biologic composition to LDE225or other agents used in the study. -Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (CoumadinÂ®) are ineligible. -Uncontrolled illness including, but not limited to, ongoing or active infection requiring IV antibiotics, symptomatic congestive heart failure not controlled with medication, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. -Pregnant women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LDE225, breastfeeding should be discontinued if the mother is treated with LDE225. -Patient has undergone a major surgery, other than diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis without removal of an organ) within four weeks prior to Day 1 of treatment on this study. -History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications. -Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE225. -Patients unwilling or unable to comply with the protocol.
Following the determination of eligibility patients will receive the following treatment: Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily. If the patient lives out of town and opts to receive gemcitabine treatment locally it will be allowed with communications between the local treating oncologist and the study team members. All treatment and doses will occur as specified in this protocol. On the first day of each cycle all patients will need to have their evaluation and treatment with the Johns Hopkins investigators in order to participate in the study. LDE225 (oral drug) will only be dispensed at Johns Hopkins Hospital. Day 8 and 15 intravenous Gemcitabine treatments can be provided locally at the doses specified on this protocol. Patients will continue taking oral LDE225 as specified in the protocol. REGIMEN DESCRIPTION AgentPremedications; Precautions Dose Route ScheduleCycle Length GemcitabineDexamethasone 12 mg PO or IV 30-60 min prior to Gemcitabine 1000 mg/m2IV Days 1, 8 and 154 weeks (28 days) LDE225Morning or PM. 600 mg PO in the a.m. Daily Dose escalation for subsequent cohort for LDE225 will occur as follows: Dose Level LDE 225 (mg)Gemcitabine (mg/m2) Level -14001000 Level 16001000 Level 28001000 Phase 2 Study: In the Phase 2 stage the patients will be randomize (1:1) to receive one of the following treatments: â?¢Arm A: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose. Cycles repeated every 28 days. â?¢Arm B: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15. Cycles repeated every 28 days. If the patient lives out of town and opts to receive gemcitabine treatment locally it will be allowed with communications between the local treating oncologist and the study team members. All treatment and doses will occur as specified in this protocol. On the first day of each cycle all patients will need to have their evaluation and treatment with the Johns Hopkins investigators in order to participate in the study. LDE225 (oral drug) will only be dispensed at Johns Hopkins Hospital. Day 8 and 15 intravenous Gemcitabine treatments can be provided locally at the doses specified on this protocol. Patients will continue taking oral LDE225 as specified in the protocol.
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