Interleukin 4 down-regulates expression of c-kit and autocrine stem cell factor in human colorectal carcinoma cells

Stem cell factor (SCF) is a cytokine which plays an important role in the development of precursor cells. We have investigated the expression of SCF and its receptor, the c-kit proto-oncogene, in human colorectal carcinoma cell lines. Using reverse transcription-PCR, we confirmed the expression of c-kit in two lines (151 74T and 151 034) and of SCF in 9 of 1 1 cell lines tested. In a Northern blot, a single transcript of 6.6 kb was detected for SCF mRNA. In addition, two lines (LS1 74T and HT29) synthesized SCF protein, as detected by Western blot analysis. SCF stimulated proliferation and colony formation of 151 74T in a dose-dependent manner up to 160%. A half-maximal effect was obtained with about 5.5 ng/ml of SCF under both growth conditions. 151 74T cells expressed the Mr 1 45,000 c-kit protein on the cell surface and a neutralizing anti-c-kit mAb inhibited colony formation of 151 74T by 40%. Interleukin 4 (11-4) completely inhibited SCF-induced proliferation of 151 74T cells. Interestingly, 11-4 induced an almost complete down-regulation of both c-kit and SCF expression in [Si 74T. Our findings suggest that in LS1 74T cells, an SCF-mediated autocrine loop is functional and that 11-4 down-regulates the expression of both the receptor and the ligand of this circuit

Panobinostat plus azacitidine in adult patients with MDS, CMML, or AML: results of a Phase 2b study

Abstract Introduction: Azacitidine (AZA) is approved for the treatment of myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML). AZA has improved the overall survival (OS) of patients (pts) with higher-risk MDS, however, to a median OS of 24.5 months (Fenaux P, et al. Lancet Oncol. 2009;10:223-232). Preclinical results showed that panobinostat (PAN), a pan-deacetylase inhibitor, acts synergistically with AZA. This is a phase 1b/2b study in adult pts with higher-risk MDS (International Prognostic Scoring System), CMML, or acute myeloid leukemia (AML) not eligible for stem cell transplant. In the phase 1b portion, the maximum tolerated dose was not reached, and the 30-mg PAN dose was chosen as the recommended phase 2 dose (Ottmann OG, et al. ASH 2011; [abstract 459]). Here we present the results from the randomized, 2-arm phase 2b portion, which was designed to assess efficacy of the combination of PAN + AZA compared with AZA alone. Methods: In phase 2b, pts were randomly assigned to receive PAN 30 mg on days 3, 5, 8, 10, 12, and 15 in combination with AZA 75 mg/m2 on days 1-7 in 4-week cycles, or AZA alone. Pts continued treatment until progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was the composite complete response: complete response (CR) + morphologic CR with incomplete blood count + bone marrow CR (BM-CR). Results: In the phase 2b portion, 82 pts with MDS (n = 47), AML with < 30% bone marrow blasts (n = 22), or CMML (n = 13) were randomized to treatment with PAN + AZA (n = 40) or AZA (n = 42); 80 pts received ≥ 1 dose of treatment. Median pt age was 68 years (range, 44-81 years) in the PAN + AZA arm vs 72 years (range, 42-85 years) in the AZA arm. Among pts with MDS, 80.0% and 72.7% had refractory anemia with excess blasts in the PAN + AZA and AZA arms, respectively. Cytogenetics among pts with AML were also similar between treatment arms, with 33.3% of pts in the PAN + AZA arm and 30.8% of pts in the AZA arm presenting with unfavorable cytogenetics. Most pts in the total study population had not received prior treatment (87.5% in the PAN + AZA arm, 92.9% in the AZA arm). Median duration of PAN treatment was 20.5 weeks; median duration of AZA treatment was 23.4 weeks in the PAN + AZA arm and 16.9 weeks in the AZA arm. A higher proportion of pts achieved composite CR in the PAN + AZA arm than the AZA arm (27.5% vs 14.3%), including a higher proportion of pts in the PAN + AZA arm who achieved CR (15.0% vs 9.5%). However, the overall response rate (ORR; CR + BM-CR + partial response + hematologic improvement) was similar in the 2 treatment arms (37.5% vs 38.1%). The probability of survival at 1 year was also similar between the 2 arms: 60% (95% CI, 50%-80%) in the PAN + AZA arm vs 70% (95% CI, 50%-80%) in the AZA arm. Most pts had ≥ 1 adverse event (AE; PAN + AZA, 100% any grade and 97.4% grade 3/4; AZA, 95.2% any grade and 81.0% grade 3/4). The most common AEs (grade 3/4) with a higher incidence in the PAN + AZA arm, regardless of study drug relationship, were thrombocytopenia (55.3% vs 19.0%), neutropenia (42.1% vs 26.2%), anemia (21.1% vs 11.9%), and pneumonia (15.8% vs 11.9%). QT prolongation-related events were reported in 13.2% of pts in the PAN + AZA arm vs 7.1% in the AZA arm. Treatment discontinuation due to AEs was reported in 36.8% of pts in the PAN + AZA arm and 23.8% of pts in the AZA arm. There were 5 on-treatment deaths (13.2%) in the PAN + AZA arm (progressive disease, sepsis, septic shock, cardiac failure, and bronchopulmonary hemorrhage) and 2 (4.8%) in the AZA arm (septicemia and cardiopulmonary arrest). One death in the PAN + AZA arm was suspected to be treatment related (bronchopulmonary hemorrhage). Conclusions: PAN + AZA doubled the rate of composite CR compared with AZA in pts with higher-risk MDS, CMML, or AML not eligible for stem cell transplant. However, the ORR and 1-year survival rates were similar for the 2 arms, with higher rates of AEs and on-treatment deaths in the PAN + AZA arm. Notably, the dose and schedule of PAN used in this study differ considerably from the dose and schedule approved for use in multiple myeloma. Therefore, in MDS, CMML, and AML, further optimization of the PAN dose and schedule in combination with AZA is needed to improve the efficacy and tolerability of this combination. Disclosures Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Graux:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavenagh:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Yee:Oncoethix: Research Funding; Astex: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zhu:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Valcarcel:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Borbenyi:Novartis: Membership on an entity's Board of Directors or advisory committees. Wegener:Novartis: Employment. Gazi:Novartis Pharma AG: Employment. Acharyya:Novartis Pharmaceuticals Corporation: Employment. Binlich:Novartis: Employment. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding

Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial

Background Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. Methods The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. Findings Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. Interpretation Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Funding Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company

Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial

Background Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. Methods The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. Findings Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. Interpretation Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Funding Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company