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A phase 1b study of the safety and tolerability of INCB039110 in combination with gemcitabine and nab-paclitaxel in subjects with advanced solid tumors
Protocol Number:
Phase I
Ross Donehower
This is a phase 1b, 2 part study consisting of a dose escalation part and dose expansion part. Part 1: The doseoptimization phase of the study will identify the MTD of INCB039110 (up to a maximum dose of 600 mg once daily) in combination with gemcitabine with nab-paclitaxel in subjects with advanced or metastatic solid tumors. Part 2: This phase will explore the safety, tolerability, PK, biomarkers, and preliminary clinical activity of the regimen identified in Part 1, in subjects with advanced or metastatic pancreatic cancer. Part 1 will be a 3 3 dose-escalation design. Subjects will be assigned into cohorts, starting with Dose Level 0, and escalating or de-escalating according to the table below. Each cohort will be observed for a minimum of 28 days before the next cohort begins enrollment. Within each cohort, subjects will be considered nonevaluable for safety and replaced if: a) they have received the specified dose of INCB039110 for less than 70% of the days during the 28-day surveillance period, or b) they have missed greater than 1 planned dose of chemotherapy (gemcitabine/nab-paclitaxel) at the assigned dose level (or with dose-reductions per package insert or institutional guidelines). Additional subjects may be enrolled to replace subjects who are nonevaluable for safety. If a DLT is observed in 1 subject (of 3 evaluable), then that cohort will be expanded to at least 6 subjects. If no additional DLTs are observed in those 3 additional subjects, dose escalation may proceed or result in cohort expansion according to a protocol-defined algorithm. If a DLT occurs in â?¥ 2 subjects in the cohort, then the MTD will be deemed to be exceeded and the next lower dose level may be expanded to 6 subjects to evaluate safety. Expansion (Part 2): Approximately 12 subjects with advanced or metastatic pancreatic adenocarcinoma will be enrolled at the dose level established in Part 1. The decision to enroll Part 2 will depend on the ongoing safety information, will be discussed by the investigator(s) and sponsor, and will consider all available safety and PK data and the suitability of the selected regimens for future Phase 2 and Phase 3 studies. Upon completion of Part 2, Part 1 may be reopened to re-explore one of the dose levels already tested (including testing with or without granulocyte colony-stimulating factor [GCSF] supportive care) or to test INCB039110 at a dose of 800 mg QD Gemcitabine as open-label, commercial product, 1000 mg/ m2 will be administered intravenously (IV) over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. nab-Paclitaxel as open-label, commercial product will be administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. The starting dose of nab-paclitaxel in Part 1 will be 125 mg/m2. The dose of nab-paclitaxel for Part 2 of the study will be the dose identified during Part 1 of the study. INCB039110 will be self-administered as a once daily (QD) oral treatment beginning on Day 2 of Cycle 1 and daily thereafter in continuous 28-day cycles. The tolerated regimen (including the MTD of INCB039110) defined during Part 1 will be used in Part 2. Based on safety assessments, individual subjects may have dose reductions of INCB039110, gemcitabine, and nabpaclitaxel during the course of treatment.
Patients with advanced solid tumor cancers including pancreatic cancer 13.0
The INCB 39110-116 study is an, open-label, phase 1b study of INCB039110 in combination with a gemcitabinecontaining regimen in subjects with advanced or metastatic solid tumor who have failed prior therapy. Part 2 of this study will be comprised exclusively of subjects with metastatic pancreatic adenocarcinoma, having received no more than one prior therapy for metastatic disease. INCB039110 represents a novel, potent, and selective inhibitor of the Janus kinase (JAKs) enzymes with selectivity for JAK1. Because JAKs serve to transduce extracellular signals from a number of cytokines and growth factors that are upregulated and thought to be involved in the pathogenesis of cancer cachexia and cancer progression, inhibition of their signaling may be therapeutic for the treatment of such conditions. JAK1 has been shown to cooperate with other JAKs to mediate the signaling of a number of inflammatory cytokines. The gemcitabine regimen chosen for this study is appropriate to the patient population in US-based studies and is consistent with established national guidelines (Masamune et al 2005, Mehta 2010, NCCN Guidelines) in which 1000 mg/m2 every week for 3 weeks every 28 days has been shown to be both tolerated and effective. The combination of gemcitabine and nab-paclitaxel has been preliminarily reported to improve the survival in advanced pancreatic cancer and is expected to become a treatment option for this disease. The recently completed Phase 3 study of the safety and efficacy of nab-paclitaxel (Von Hoff et al 2013) indicated that a dose of 125 mg/m2 is tolerated by most patients. Because significant overlapping toxicities are not expected, the study will evaluate safety of INCB039110 in combination with a clinically standard dose of gemcitabine plus nab-paclitaxel, unless an unexpected interaction is revealed. For the treatment of solid tumors, the maximum individually tolerated dose of INCB039110 that spares inhibition of JAK2 should provide the best chance of efficacy while minimizing the potential for side effects (eg, myelosuppression). The maximum tolerated dose for healthy subject, using the current formulation, is 600 mg BID; a dose at which JAK2 inhibition is observed. In ongoing studies of INCB039110 in subjects with myelofibrosis, rheumatoid arthritis, and psoriasis, doses of 100 mg QD, 300 mg QD, 600 mg QD, 100 mg BID, 200 mg BID, and 400 mg BID have been evaluated. All of these doses have generally been safe and well tolerated, with evidence of JAK2 inhibition seen at doses â?¥ 400 mg BID. Significant anti-inflammatory activity has been seen with doses of 200 mg BID and 600 mg QD, with little evidence of JAK2 inhibition (see Section 4.3.4), indicating robust inhibition of JAK1/STAT3 signaling at these doses. Based on these data, the dose of 400 mg QD has been selected to evaluate the hypothesis that JAK1 inhibition alone is sufficient to improve survival by blocking JAK1/STAT3 signaling, with potential effects on cachexia and direct antitumor effects, as noted above, in patients with pancreatic adenocarcinoma. Because of limited JAK2 activity at this dose, and evidence of tolerability at this exposure level in bone marrowâ??fragile myelofibrosis patients, 400 mg QD is expected to be tolerated in combination with the gemcitabine nab-paclitaxel regimen. If 400 mg QD is tolerated, higher doses (600-800 mg QD) may be explored. If 400 mg QD is not tolerated in combination with gemcitabine and nab-paclitaxel, a lower dose of 300 mg QD will be evaluated, which still should have sufficient JAK1 inhibition to test the hypothesis. It is not anticipated that doses of INCB039110 below 300 mg QD will be generally effective; therefore, lower doses will not be used in this study. If this regimen is not tolerated, the INCB039110 dose will be held at 300 mg QD and evaluated in combination with gemcitabine 1000 mg/m2 and nab-paclitaxel 100 mg/m2, as this regimen also has demonstrated significant antitumor activity. If further dose decreases are needed, INCB039110 400 mg QD will be evaluated with gemcitabine 1000 mg/m2 to minimize bone marrow toxicity. Given the manifestations of cachexia in patients with pancreatic adenocarcinoma and the resulting poor tolerance of anticancer therapy, we hypothesize that the addition of INCB039110 to gemcitabine with or without nab-paclitaxel therapy may confer clinical benefit leading to the alleviation of symptoms and improvement in overall survival. Gemcitabine is a reasonable choice for combination therapy as first- or second-line therapy, and gemcitabine plus nabpaclitaxel is emerging as a new combination treatment for pancreatic cancer. In the current study, the combination of INCB039110/gemcitabine with or without nab-paclitaxel will be evaluated to test the hypothesis that the medications can be administered safely in combination.
Last Update
07/22/2014 04:02 AM

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