Trial Of Ruxolitinib In Combination Research Articles

Abstract P2-07-04: Analysis of host inflammatory and estrogen biomarkers in JAKEE: A phase II trial of the JAK inhibitor ruxolitinib in combination with exemestane for estrogen receptor-positive metastatic breast cancer

Abstract Background: Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor outcomes and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) metastatic breast cancer (MBC). We previously presented clinical outcomes of JAKEE, a single arm, phase II, Simon two-stage clinical trial that tested Ruxolitinib (Rux), an oral selective inhibitor of JAK1/2, and exemestane (EXE) in 25 participants (pts) with HR+ MBC that relapsed/progressed on non-steroidal AI (NSAI); specifically, the primary endpoint of safety was met, but there were no complete or partial responses and 6/25 (24%) achieved stable disease (SD) for ≥6 cycles. We investigated whether host circulating inflammatory markers, IL-6 genotypes, and estrogen levels were associated with differential response to therapy.Methods: Responders (R) were defined as having achieved SD≥6 cycles. Flow cytometry was performed on baseline and on-treatment peripheral blood samples to assess downstream CD3+ T-cell phosphoSTAT3 inhibition by Rux. Serum concentrations of C-reactive protein (CRP), IL-6, serum amyloid A (SAA), Estrone (E1) and Estradiol (E2) were measured at baseline and serially on treatment. Sanger sequencing was performed to assess for three functional variants of the IL-6 promoter: −572G>C (rs1800796), −597G>A (rs1800797), and −174G>C (rs1800795), with high-risk polymorphisms being -597G/G and/or -174G/G. Non-parametric median testing was employed to test for differences in circulating markers by response groups given non-normal distribution, with a two-sided alpha of 0.05.Results: The cohort was heavily pre-treated: 28% received ≥2 lines of chemotherapy for MBC and 20% had CNS disease at enrollment. Among 17/25 pts with samples for pharmacodynamic assessment, Rux exhibited a 25% median inhibition (range 0-77%) of phosphoSTAT3. There was no differential effect in R vs non-responders (NR) (median inhibition 20% vs 29%, p=0.15). Frequency of high-risk IL-6 genotypes and distribution of baseline serum CRP, IL-6, SAA, E1 and E2 are depicted in the table. 15/25 (60%) harbored a high-risk IL-6 promoter polymorphism, with no significant difference in frequency between R and NR (50% vs 63%, p=0.65). 19 pts had samples for inflammatory biomarker analysis. 16/19 had baseline CRP≥10mg/L. While median levels of baseline CRP, SAA, and IL-6 were above upper limit of normal, there was no difference between R and NR (table). The proportion of pts with baseline undetectable E1 and E2 were similar between R and NR (E1: 36.9% vs 33.3%, p=1.0, E2: 52.6% vs 50%, p=1.0); notably, a significantly lower proportion with high-risk IL-6 genotype had undetectable baseline E1 (20% vs 60%, p=0.041), while no difference was noted for baseline E2, nor in the % change in E1 or E2 levels from baseline to cycle 4 by responder status.Conclusions: The JAKEE cohort represents an inflamed population with elevated circulating inflammatory markers and a high proportion with high-risk IL-6 genotypes. Examination of host inflammatory markers, IL-6 genotypes and estrogen levels did not reveal a differential response to the combination of Rux and EXE in patients with HR+ MBC that had progressed on prior NSAI. At tolerable dosing, Rux exhibited only a modest inhibition of phosphoSTAT3. Further work is needed to optimize strategies for targeting inflammation and JAK/STAT signaling in HR+ MBC. IL-6 GenotypeFrequencyFrequency by ResponderSignificanceHigh-Risk -174G/G and/or -597G/G15/25 (60%)Non-responder12/19 (63.2%)Responder3/6 (50%)p-value0.56Pretreatment Inflammatory Biomarkers [Upper limit of normal]Median (Range)Median Level by Responder GroupSignificanceCRP [8mg/L]SAA [10mg/L]IL-6 [2pg/mL]24.0 (0.2-146.8)12.8 (2.8-162.5)4.2 (1.8-11.5)Non-responder23.219.84.5Responder24.7 12.42.7p-value0.510.150.15Baseline Estrogen BiomarkersMedian (Range)Non-responderResponderp-valueEstrone (E1) (pg/mL)Estradiol (E2) (pg/mL)79.5.0 (0.2-1039.0)0.2 (0.2-44.1)79.8 0.247.8 4.20.410.91 Citation Format: Igor Makhlin, Nicholas McAndrew, E. Paul Wileyto, Amy Clark, Robin Holmes, Lisa N Bottalico, Grace R Jeschke, Kevin R Fox, Susan M Domcheck, Jennifer M Matro, Angela R Bradbury, Natalie Shih, Michael D Feldman, Elizabeth O Hexner, Jacqueline F Bromberg, Angela DeMichele. Analysis of host inflammatory and estrogen biomarkers in JAKEE: A phase II trial of the JAK inhibitor ruxolitinib in combination with exemestane for estrogen receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-04.

Abstract P1-19-32: Phase I/II trial of ruxolitinib in combination with trastuzumab in HER2+ metastatic breast cancer (MBC)

Abstract Background: Preclinical and clinical studies suggest that trastuzumab resistance in HER2+ BC is mediated by cross-activation of alternative signaling pathways. Computational analysis and pooled whole-genome RNAi screens in HER2 transformed BC cell lines identified the IL6/JAK2/STAT3 axis as a master regulator pathway. The combination of trastuzumab plus ruxolitinib, a JAK1/JAK2 inhibitor, demonstrated synergistic tumor growth inhibition in mouse xenografts of HER2 transformed BC cell lines. These data provide the rationale for studying the efficacy of ruxolitinib and trastuzumab in a phase I/II trial. Design: This is an investigator-initiated, multi-center, open-label, phase I/II trial of ruxolitinib plus trastuzumab in patients (pts) with HER2+ MBC who have progressed on >2 HER2-directed therapies in the metastatic setting (including trastuzumab, pertuzumab and T-DM1, unless pt refusal). The phase I is an adaptive design with 10 pts to determine the recommended phase II dose (RP2D: 25 mg po BID, SABCS 2017). Phase II is a non-randomized open-label trial of 30 pts with trastuzumab plus ruxolitinib to compare progression free survival (PFS) against historical data with single-agent HER2-targeted therapy in HER+ MBC (Blackwell JCO 2010). The study was powered to detect a difference in median PFS of 8 weeks versus 13 weeks. Response was assessed by imaging every 9 weeks. Results: We accrued 28 pts from 10/14-8/18 and stopped early due to slow accrual. Of the 27 evaluable pts, 11 were in the phase I, of which 10 pts received 25 mg po BID (RP2D). Thus, 26 pts are included in the phase 2 study (pre-specified). Of the evaluable pts, the median age was 56 (range 32 - 77). Of these, 24 pts were postmenopausal (92%), 15 (58%) were estrogen receptor positive, and 24 (92%) had measurable disease, including 8 (33%) in lung and 4 (15%) in liver. The median number of prior lines of therapy in the metastatic setting was 4 (range: 2-9). Twenty-three pts (88.5%) received prior pertuzumab and 25 (96.1%) received prior T-DM1. As of 6/24/19, 2 pts remain on therapy at 46 and 72 weeks of follow-up. Twenty evaluable pts came off study due to progression, 3 due to death from disease, and 1 for adverse events. The median PFS was 10.7 weeks (95% CI: 7.1-15.1). The 6-month PFS is 21% (7%, 40%). The most common treatment-related adverse events (AEs) were hematologic [anemia 13 (50%), neutropenia 10 (38%), thrombocytopenia 8 (31%)], fatigue 9 (35%), aspartate aminotransferase increase 4 (15%) and diarrhea 4 (15%). The most common grade 3 AEs were anemia 7 (27%), and neutropenia 6 (23%). Grade 4 or higher events were not observed. Response data in pts with measurable disease will be presented at SABCS. Conclusion: Ruxolitinib plus trastuzumab was a well-tolerated regimen that does not include cytotoxic chemotherapy. While the combination did not achieve the primary endpoint (median PFS), there was 6-month PFS of 21% in this heavily pre-treated HER2+ MBC population. Ongoing analyses will be done to determine factors that predict clinical benefit. Citation Format: Kevin Kalinsky, Shing Lee, Amy Tiersten, Della F Makower, Tessa Cigler, Lauren Franks, Prabhjot Mundi, Dow-Chung Chi, Lauren Blumberg, Naomi Sender, Magdalena Galazyn, Kristina Hosi, Anupama Goel, Paula Klein, Eleni Andreopoulou, Joseph Sparano, Katherine D Crew, Andrea Califano, Jose Silva, Dawn L Hershman. Phase I/II trial of ruxolitinib in combination with trastuzumab in HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-32.

Conventional Real Time Quantitative Polymerase Chain Reaction Method Yields Similar Level of Sensitivity to Digital Droplet Polymerase Chain Reaction for Detection of BCR-ABL p210 Transcripts in Patients with Chronic Phase Chronic Myeloid Leukemia

Introduction: Several studies have investigated the utility of digital droplet polymerase chain reaction (ddPCR) in the detection of p210 BCR-ABL fusion transcripts in chronic myeloid leukemia (CML), and have suggested greater sensitivity compared to real-time quantitative PCR (RT-qPCR). There is limited data regarding the utility and sensitivity of ddPCR in patients with chronic phase CML (CP-CML) who are candidates for tyrosine kinase inhibitor (TKI) discontinuation. We aimed to investigate the capability of ddPCR to detect p210 BCR-ABL transcript levels in CP-CML patients and compare the sensitivity to RT-qPCR. Methods: We analyzed 103 different peripheral blood (n=98) and bone marrow (n=5) samples from 36 patients with CP-CML treated at Moffitt Cancer Center between 2013 and 2018. Samples were from patients who either met clinical criteria for TKI discontinuation or were enrolled in a phase I dose-escalation study evaluating combination therapy with nilotinib plus ruxolitinib who had at least a complete cytogenetic response (CCyR) to TKI therapy with detectable BCR-ABL transcripts by RT-PCR at the time of enrollment(1, 2). BCR-ABL levels were assessed by RT-qPCR at the time of collection with level of transcript reported as % International Standard (%IS). Samples collected from 2013 to 2014 were reported as p210 to ABL and converted to %IS per lab-specific conversion factor. Stored purified RNA samples were obtained retrospectively and ddPCR was performed using the QX-200 Droplet Digital PCR System and QXDx BCR-ABL %IS Kit (Bio-Rad). Droplets were analyzed by QXDx BCR-ABL reporter software to determine p210 transcript level (%IS). Analysis for RNA degradation of stored samples was performed via High Sensitivity RNA ScreenTape (Agilent). Samples that did not pass quality check upon performing ddPCR were excluded from further analysis. Correlation coefficient was calculated with p-value of <0.05 being significant. Results: Of the 36 patients, 28 were in the TKI discontinuation cohort and 10 were enrolled in the clinical trial of nilotinib plus ruxolitinib. Two patients who participated in the clinical trial subsequently also met criteria for TKI discontinuation. In the TKI discontinuation cohort, 46% of patients (n=13) lost major molecular response (MMR) with a median time to loss of MMR of 88 days. We observed a statistically significant correlation between RT-qPCR and ddPCR levels when comparing %IS (correlation coefficient R2=0.42; p<0.0001) as well as calculated molecular response (MR) logarithm values of all available samples (R2=0.67; p <0.0001) (Figure 1). There was a weaker correlation between patients determined to have MMR by RT-qPCR (MR≥3.0) compared to ddPCR (R2=0.55; p <0.0001) (Figure 2). A total of 91 different samples were consistent with MMR when tested by RT-PCR. Of these samples, 85.7% (n=78) were consistent with MMR when tested by ddPCR and the remaining 14.3% (n=13) appeared to have higher detectable levels of p210 transcripts (MR<3.0). When investigating deeper molecular responses, 62 samples were consistent with MR≥4.0 by RT-PCR, and 20.9% (n=13) of these samples did not achieve a deep molecular response (MR<4.0) when tested by ddPCR. Of note, 5 representative samples were also evaluated for potential RNA degradation and 3 were noted to have significant degradation present. Conclusion: Compared to RT-PCR, ddPCR represents a viable method for detection of p210 transcripts for patients with CP-CML. The two methods yield similar efficacy when detecting varying levels of molecular response, however further research is warranted for the ability to detect deeper molecular responses for patients in MMR. Our study is limited by inherent retrospective bias and quality of RNA in stored samples. 1. National Comprehensive Cancer Network. Chronic Myeloid Leukemia (Version 1.2019). 2. Sweet K, Hazlehurst L, Sahakian E, Powers J, Nodzon L, Kayali F, et al. A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic myeloid leukemia patients with molecular evidence of disease. Leuk Res. 2018;74:89-96. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. Shelton:Bio-Rad: Employment. Nodzon:Pharmacyclics: Consultancy; Abbvie: Other: Speaker Fees; Genentech: Consultancy, Other: Speaker Fees; Pfizer: Consultancy. Sweet:Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Pinilla Ibarz:Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Sanofi: Speakers Bureau.

Phase 2 Study of Ruxolitinib (RUX) in Combination with 5-Azacitidine (AZA) in Patients (pts) with Myelofibrosis

Phase 2 Study of Ruxolitinib (RUX) in Combination with 5-Azacitidine (AZA) in Patients (pts) with Myelofibrosis

A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

A Phase I-II Study of Ruxolitinib (INCB18424) for Patients with Chronic Myeloid Leukemia with Minimal Residual Disease While on Therapy with Imatinib

A Phase I-II Study of Ruxolitinib (INCB18424) for Patients with Chronic Myeloid Leukemia with Minimal Residual Disease While on Therapy with Imatinib

A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic myeloid leukemia patients with molecular evidence of disease

PurposePreclinical evidence indicates that the bone marrow microenvironment provides a protective niche for leukemic stem cells, allowing them to evade the effects of BCR-ABL tyrosine kinase inhibitors (TKIs), but that targeting of the JAK-STAT pathway with the JAK2 inhibitor ruxolitinib increases TKI-induced apoptosis. A phase I clinical trial (NCT01702064) investigated the tolerability and safety of treating chronic-phase chronic myeloid leukemia patients with ruxolitinib in combination with the BCR-ABL TKI nilotinib and explored initial efficacy evidence. Experimental designEleven patients already treated with single-agent nilotinib (300–400 mg twice daily) commenced combination therapy, and molecular responses were evaluated after 6 months. Three ruxolitinib dose cohorts were studied: 5 mg, 10 mg, and 15 mg twice daily. ResultsOne patient experienced a grade 3/4 adverse event (hypophosphatemia) and 36% of patients experienced grade 1/2 anemia. Of 10 patients who were evaluable for responses, 40% had undetectable BCR-ABL transcripts, as measured by quantitative RT-PCR after 6 months. Plasma inhibitory assay results revealed a decrease in phospho-STAT3 levels after treatment with ruxolitinib. The recommended phase 2 dose of ruxolitinib was 15 mg BID. ConclusionsOverall, this combination was safe and well-tolerated, and the molecular responses were encouraging, thereby warranting further investigation in a phase 2 trial.

Abstract P4-21-37: Phase I trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract Background Preclinical and clinical studies suggest that trastuzumab resistance in HER2 amplified breast cancer (HER2+ BC) is mediated by cross-activation of alternative signaling pathways. Computational analysis and pooled whole-genome RNAi screens in HER2 transformed BC cell lines identified the IL6/JAK2/STAT3 axis as a master regulator pathway. The combination of trastuzumab plus ruxolitinib, a JAK1/JAK2 inhibitor, demonstrated synergistic tumor growth inhibition in mouse xenografts of HER2 transformed BC cell lines. These data provide the rationale for studying the efficacy of ruxolitinib and trastuzumab in a clinical trial. Design This is a multi-center, open-label, phase I/II trial of ruxolitinib plus trastuzumab in patients (pts) with HER2+ metastatic BC (MBC) who have progressed on >2 HER2-directed therapies in the metastatic setting (including trastuzumab, pertuzumab and T-DM1). The phase I is an adaptive design with 10 pts, using the time-to-event continual reassessment method to determine the recommended phase II dose. Phase II will be a non-randomized, open-label trial with 30 evaluable pts. The duration of a treatment cycle is 21 days, with trastuzumab given on Day 1 and ruxolitinib taken orally twice daily continuously. The primary endpoint of phase I is to determine the maximum tolerated dose of the drug combination. The phase I dose range for ruxolitinib is 10-25 mg BID (dose level 0: 20 mg BID). Response is assessed by imaging every 9 weeks. Blood samples and optional tissue biopsies are obtained for biomarker analysis at the following time points: pre-treatment, on-treatment C2D1, and at progression. Results Phase I started accrual in the fall of 2014. The trial has accrued 12 patients, with 9 evaluable and 3 non-evaluable patients. Of the evaluable patients, the mean age was 55.9 (range 32-69). Of these, 7 were postmenopausal (78%) 5/9 (56%) were estrogen receptor positive, and all had measurable disease. The mean number of prior lines of therapy in the metastatic setting was 5.6 (range: 3-8), including a mean of 3.2 (range: 2-5) prior regimens containing HER2 targeted therapies. As of 6/12/16, 2 patients remain on therapy. As this is an adaptive design, efficacy and drug tolerability will not be mentioned in this abstract to not bias the ongoing analysis. However, we anticipate that by SABCS 2016, 10 evaluable patients will have completed the DLT period – at which point, complete data will be presented. Conclusion Ruxolitinib plus trastuzumab is a novel, non-chemotherapy containing regimen. The phase I analysis is ongoing. We plan on reporting full safety/tolerability and efficacy data once 10 evaluable patients have completed the phase I (9/10 have currently completed DLT period). Given an early signal in HER2+ breast cancer, in this heavily pretreated population we will proceed directly to a phase II trial with the combination. Citation Format: Mundi PS, Lee S, Chi D, Bhardwaj A, Makower D, Cigler T, Crew KD, Hershman DL, Califano A, Silva J, Kalinsky KM. Phase I trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-37.

Abstract P2-08-03: Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer

Abstract Background: In vitro mechanisms link IL-6 to poor outcome in breast cancer via inflammatory pathways, activated JAK/STAT tumor signaling and upregulation of aromatase, leading to an aggressive tumor phenotype. Epidemiological data from our group and others support these mechanisms in women with ER-positive (+) disease. We therefore hypothesized that the JAK inhibitor, ruxolitinib (RUX, INCB018424; Incyte), would enhance activity of exemestane (EXE) in women with ER+ breast cancer who relapsed after non-steroidal aromatase inhibitor therapy, particularly among carriers of a germ-line polymorphism in IL-6, conferring elevated levels of IL-6 in the tumor microenvironment. Methods: The “JAKEE trial” is a phase II trial to determine the safety and efficacy of RUX + EXE in postmenopausal women with relapsed, ER+ advanced breast cancer. Eligible patients were required to have progressed on a non-steroidal AI and either measureable or bone-only disease. CRP, a putative biomarker of tumor microenvironment inflammation, was measured at baseline and serially during treatment. Using a Simon 2-stage design, we treated 15 patients with RUX at 25 mg BID and EXE at 25mg daily on a continuous 28-day schedule. First stage results were previously presented (AACR, 2014). Accrual proceeded to second stage after no patient met the pre-defined stopping rule of grade (G) 3/4 toxicity requiring discontinuation from the study within the first treatment cycle. Due to the substantial rate of anemia requiring dose reductions, however, RUX dose was reduced to 15 mg BID in second stage. Results: A total of 25 patients were enrolled; 24/25 had progressed on AI in metastatic setting; 1 relapsed on adjuvant AI. RUX+EXE was well-tolerated overall, with only 2 G4 events (creatinine elevation, hepatic failure); both were due to disease progression. 16% had G3 fatigue, anemia or hypertension; 12% had G3 neutropenia or depression. Other lower grade toxicities in >20% included musculoskeletal pain, increased ALT, and headache. Overall, patients stayed on therapy for a median of 3 cycles (range 2 – 21). There were no CR or PR, but 6/25 (24%) had prolonged disease control (SD> 6 months). Median CRP at study entry was 6.4 (range 0.3-38.9), with 8/25 (32%) having CRP>10. Achieving SD>6 months was not associated with baseline CRP (CRP>10 in 32% with vs. 33% without SD>6 months, p(exact)=1.0). A novel pharmacodynamic assay to assess STAT3 phosphorylation in peripheral blood mononuclear cells after RUX exposure demonstrated differential effects in patients with response. Conclusions: Targeting JAK/STAT signaling in AI-resistant breast cancer with RUX+EXE was safe and well-tolerated. 24% of patients had prolonged SD, but baseline CRP level did not predict response. Correlative studies to determine whether host and/or tumor biomarkers predict response to therapy, including germline IL-6 genotype, immune profiles, p-STAT3 and estradiol levels, are currently underway. Citation Format: DeMichele AM, Clark AS, Holmes R, Volpe M, Medrano C, Troxel A, Fox K, Domchek S, Matro J, Bradbury A, Shih N, Feldman M, Hexner E, Bromberg J. Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-03.

Abstract OT3-01-06: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract Background: Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Trial Design: A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be an adaptive design with 10 patients, using the time-to-event continual reassessment method. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients (pts). Given the anticipated limited overlapping toxicities, approximately 36 pts (range: 32-40) are expected for the P1/2. The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID (dose level 0: 20 mg BID). T will be administered on Day 1 of each cycle at standard dosing. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis, pre-treatment, on-treatment on C2D1, and then at progression. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy on C2D1, and upon progression of disease will be discussed with pts with accessible disease. Main Eligibility Criteria: 1. HER2 positive MBC 2. Progression on HER2-directed therapy in metastatic setting, including Pertuzumab and T-DM1 3. Measurable or non-measurable disease 4. LVEF great than 50% 5. No history of prior JAK2 inhibitor 6. No HIV-positive or active infection 7. No concurrent medications that are potent CYP3A4 inhibitor or inducer Specific Aims: 1. Primary: P1: MTD of combined R + T. P2: Progression Free Survival (PFS) 2. Secondary: a) Clinical: ORR, clinical benefit rate (CBR), and tolerability. Pts will be stratified by hormone receptor (HR) status to explore differences in efficacy between HR+ and HR-. b) Explore potential predictive tumor and blood-based predictive biomarkers at baseline, on treatment, and progression: (tumor: pSTAT3 expression); serum: IL-6, IL-8, C-reactive protein; circulating tumor cell pSTAT3 expression; and tumor gene expression. Statistical Methods: Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that pts receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Target Accrual: Sample Size: 32-40 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Trial accruing since Fall 2014. Citation Format: Kalinsky K, Chi D-C, Lee S, Bhardwaj A, Makower D, Cigler T, Crew KD, Hershman DL, Califano A, Silva J, Maurer M. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-06.

Abstract OT1-1-09: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract Background Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Trial Design A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be an adaptive design with 10 patients, using the time-to-event continual reassessment method. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients (pts). Given the anticipated limited overlapping toxicities, approximately 36 pts (range: 32-40) are expected for the P1/2. The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID (dose level 0: 20 mg BID). T will be administered on Day 1 of each cycle at standard dosing. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis, pre-treatment, on-treatment on C2D1, and then at progression. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy on C2D1, and upon progression of disease will be discussed with pts with accessible disease. Main Eligibility Criteria: 1. HER2 positive MBC 2. Progression on >2 HER2-directed therapy in metastatic setting, including Pertuzumab and T-DM1 3. Measurable or non-measurable disease 4. LVEF >50%. 5. No history of prior JAK2 inhibitor 6. No HIV-positive or active infection 7. No concurrent medications that are potent CYP3A4 inhibitor or inducer Specific Aims 1. Primary: P1: MTD of combined R + T. P2: Progression Free Survival (PFS) 2. Secondary: a) Clinical: ORR, clinical benefit rate (CBR), and tolerability. Pts will be stratified by hormone receptor (HR) status to explore differences in efficacy between HR+ and HR-. b) Explore potential predictive tumor and blood-based predictive biomarkers at baseline, on treatment, and progression: (tumor: pSTAT3 expression); serum: IL-6, IL-8, C-reactive protein; circulating tumor cell pSTAT3 expression; and tumor gene expression. Statistical Methods Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that pts receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Target Accrual Sample Size: 32-40 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Trial will start accruing July 2014. Citation Format: Kevin Kalinsky, Dow-Chung Chi, Shing Lee, Amy Tiersten, Della Makower, Ellen Chuang, Katherine D Crew, Dawn L Hershman, Jose Silva, Andrea Califano, Matthew Maurer. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-09.

Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2-positive breast cancer.

TPS666 Background: Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for ...

Abstract OT2-6-05: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract Background Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Trial Design A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be a dose-escalation study with a 3 + 3 design to determine maximum tolerable dose (MTD) for the combination. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients (pts). Given the anticipated limited overlapping toxicities, 33 pts are expected for the P1/2 (range: 33-42 pts). The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID (dose level 0: 20 mg BID). T will be administered on Day 1 of each cycle at standard dosing. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis, pre-treatment, on-treatment on C1D8, and then every 9 weeks. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy after C1, and upon progression of disease will be discussed with pts with accessible disease. Main Eligibility Criteria: 1. HER2 positive MBC 2. Progression on at least one T-containing regimen in the metastatic setting 3. Measurable or un-measurable disease 4. LVEF >50% 5. No history of prior JAK2 inhibitor 6. No HIV-positive or active infection 7. No concurrent medications that are potent CYP3A4 inhibitor or inducer Specific Aims 1. Primary: P1: MTD of combined R + T. P2: Progression Free Survival (PFS) 2. Secondary: a) Clinical: ORR, clinical benefit rate (CBR), and tolerability. Pts will be stratified by hormone receptor (HR) status to explore differences in efficacy between HR+ and HR-. b) Explore potential predictive tumor and blood-based predictive biomarkers at baseline, on treatment, and progression: (tumor: pSTAT3 expression); serum: IL-6, IL-8, C-reactive protein; circulating tumor cell pSTAT3 expression; and tumor gene expression. Statistical Methods Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that pts receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Target Accrual Sample Size: 33-42 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Contact Kevin Kalinsky/ Matt Maurer kk2693@columbia.edu/mm2058@columbia.edu. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-05.