Final Dose Level Research Articles

A Phase 1/2 Study of Carfilzomib, Iberdomide and Dexamethasone (KID) in Patients with Newly Diagnosed Transplant-Eligible Multiple Myeloma

Background: Iberdomide is a next generation cereblon-E3 ligase modulating agent (CELMoD) that has increased antitumor activity relative to earlier thalidomide analogs (IMiDs). This is due to direct effects on tumor cells and increased immune surveillance. Herein, we report preliminary dose escalation, safety and efficacy data from this ongoing investigator-initiated study of carfilzomib (CFZ), iberdomide, and dexamethasone (DEX) (KID) as induction therapy in patients with transplant-eligible, newly diagnosed multiple myeloma (NDMM). Methods: This multicenter trial included a phase 1 dose escalation study to determine the maximum tolerated dose (MTD) of iberdomide in combination with CFZ and DEX, followed by a phase 2 dose expansion study. Key inclusion criteria included NDMM, eligible for autologous stem cell transplantation (ASCT), ECOG performance status 0-2, and ≤1 cycle of prior induction therapy. In phase 1, patients were enrolled in a standard 3+3 design starting with iberdomide 1 mg on D1-21 of C1-4 in combination with CFZ (IV; 20 mg/m 2 on C1D1; 56 mg/m 2 C1D8, D15; 56 mg/m 2 C2-4, D1, 8, 15) and DEX (40 mg or 20 mg if >75 years on C1-4, D1, 8, 15) in 28-day cycles (Figure 1). Iberdomide dose escalation to 1.3 mg and 1.6 mg (maximum dose) occurred in subsequent cohorts based on the absence of dose-limiting toxicities (DLTs). Phase 1 is complete and there is ongoing enrollment in the phase 2 study. The phase 1 primary objective was to determine the safety and tolerability of KID. The phase 2 primary objective is to evaluate the rate of complete remission (CR) + stringent CR (sCR) after 2-4 cycles of KID. Patients could collect stem cells and undergo ASCT after 2-4 cycles of KID at physician's discretion. Secondary objectives include the overall response rate (ORR) and progression-free survival (PFS). Results: At data cutoff (July 14, 2023), there were 13 patients enrolled, which included 11 and 2 patients enrolled in the phase 1 and 2 studies, respectively. Ten patients are on trial, 2 were screen failures, and 1 is in screening. Of the 10 patients on trial, the median age was 66 years (range 46-78), 40% male, 70% white, and 30% had ISS stage II MM. Four unique patients had high-risk cytogenetics, which included 2 patients with t(4;14), 2 with 1q21 duplication, 1 with t(14;16), 1 with del(17p)/monosomy 17, and 1 with TP53 mutation. In the phase 1 study, 3 patients enrolled at the starting dose level of iberdomide 1 mg. Grade 1-2 TEAEs occurred in all 3 patients, but no DLTs occurred. The next 3 patients were enrolled at the iberdomide dose of 1.3 mg. Grade 1-2 TEAEs occurred in 2 patients (rash and pruritus), but no grade ≥3 TEAEs were observed. Three patients were enrolled into the final dose level of iberdomide 1.6 mg. Grade 1-2 TEAEs occurred in 2 patients, and 2 patients experienced grade 3 TEAEs (rash and neutropenia). As no DLTs occurred, the MTD of iberdomide was determined to be 1.6 mg given in combination with CFZ and DEX. Patients on trial (n=10; 6 in follow-up and 4 actively receiving treatment) have completed a median of 3 (range 2-4) cycles of KID. Of these patients, 7/10 experienced TEAEs (Table 1). No treatment-related deaths occurred. The most common TEAEs were maculopapular rash (46%), elevated liver function tests (38%), gastrointestinal symptoms (31%), and neutropenia (23%). Grade 3 TEAEs occurred in 2 patients (rash and neutropenia). One patient experienced a SAE of erythema multiforme on two separate occurrences (grade 1 and grade 2), which resolved with drug interruption. In 9 patients with response data available, the best ORR was 100% (CR, 1 [12%]; very good partial response [VGPR], 4 [44%]; partial response [PR], 4 [44%]). Six patients proceeded to ASCT with a median amount of stem cells mobilized of 9.42 x 10 6 cells/kg (range 4.84-13.53). At 3-months post-ASCT, the ORR was 100% (CR, 3 [50%]; VGPR, 2 [33%]; PR, 1 [17%]). One patient had documented sCR and MRD-negativity at data cutoff. Median PFS was not reached (NR) (95% CI, NR-NR). Conclusions: Induction therapy with KID appears safe with the only grade 3 TEAEs reported being rash and neutropenia. In patients who completed treatment, induction cycles with KID did not interfere with stem cell mobilization. Correlative and additional clinical data are being collected and will be presented. Clinical trial information: NCT05199311.

Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis.

The first-line treatment for Cushing's disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response. We searched for articles that evaluated ketoconazole use in Cushing's disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels. After applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism. Ketoconazole can be considered a safe and efficacious option for Cushing's disease treatment after pituitary surgery. https://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).

Ustekinumab levels in pregnant women with inflammatory bowel disease and infants exposed in utero.

Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P=0.83, n=11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26-3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r=0.75, P=0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r=-0.65, P=0.006). Median time of infant ustekinumab clearance was 9 (range 6-19) weeks (n=9). Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12months of age until further clearance data are obtained.

Abstract PS10-26: An initial safety study of gedatolisib plus cofetuzumab pelidotin for metastatic triple-negative breast cancer

Abstract Background: The PI3K pathway is dysregulated in the majority of triple-negative breast cancer (TNBCs), yet single agent inhibition of PI3K in TNBC has minimal clinical activity. We previously reported that PI3K inhibition leads to an immediate compensatory up-regulation of the Wnt pathway. Dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo. We initiated a Phase I clinical trial of gedatolisib, a pan-class I isoform PI3K/mTOR inhibitor, and cofetuzumab pelidotin, an antibody-drug conjugate against the cell-surface PTK7 protein (Wnt pathway co-receptor) with an auristatin payload. PTK7 is up-regulated after PI3K inhibition and auristatin is in itself synergistic with gedatolisib providing the potential for a dual mechanism of synergy. Methods: Dose escalation proceeded using a traditional 3+3 schema with a small expansion cohort at the final dose level to better characterize safety. Participants had metastatic TNBC or ER low (ER and PgR <5%, HER2 negative) breast cancer, and had received at least one prior line of chemotherapy. The primary objective was safety. Secondary endpoints included objective response (ORR), clinical benefit at 18 weeks (CB18), and progression-free survival (PFS). Exploratory analyses probed the association of tumor DNA, RNA, and IHC with clinical efficacy to identify putative biomarkers. Results: Between January 2018 and January 2020, 18 patients were enrolled in 3 dose cohorts: gedatolisib (qw) & cofetuzumab pelidotin (q3w) 110mg+1.4mg/kg (n=4), 180mg+1.4mg/kg (n=3), and 180mg+2.8mg/kg dose levels (n=11). The median age was 53 years (32-77). Nausea (n=16), anorexia (n=13), fatigue (n=12), and mucositis (n=12) were common but rarely reached >Grade 3 severity (nausea, n=1; fatigue, n=2). Myelosuppression was uncommon (Grade >3 neutropenia, n=2). 16 participants were evaluable for response. 3 achieved a confirmed partial response (PR), and 3 had stable disease (SD). ORR=18.8%. All 3 PRs lasted > 6 months. CB18=31.3%. Median PFS was 2.0 months (95% CI for PFS:1.2-6.2); median OS was 9.5 months (95% CI for OS:4.3-not reached). Correlative analyses of genomic, transcriptomic, and protein biomarkers with response are currently ongoing. Conclusions: The combination of gedatolisib + cofetuzumab pelidotin for the treatment of metastatic TNBC was found to be well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted. Trial Registration: NCT03243331 Citation Format: Milan Radovich, Jeffrey P. Solzak, Bradley A. Hancock, Sunil Badve, Anna Maria V. Storniolo, Tarah J. Ballinger, Bryan P. Schneider, Kathy D. Miller. An initial safety study of gedatolisib plus cofetuzumab pelidotin for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-26.

Abstract PR09: Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. As a metabolite, glutamine is first converted to glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers, including 20-30% of colorectal cancer (CRC). We found that oncogenic PIK3CA mutations render CRCs addicted to glutamine through an upregulation of glutamate pyruvate transaminase 2 (GPT2), thereby facilitating conversion of glutamate to α-KG. Here, we report that CB-839, a potent GLS inhibitor developed by Calithera Biosciences, inhibits xenograft tumor growth of PIK3CA mutant, but not WT, colorectal cancers. Remarkably, combination of CB-839 with 5-fluorouracil (5-FU) induces regression of xenograft tumors in four different PIK3CA mutant CRC models. These exciting preclinical data prompted us to perform a phase I and phase II clinical trial to assess combination of CB-839 with capecitabine, an oral prodrug of 5-FU. For the phase I trial, patients with advanced solid tumors and disease progression on standard treatment, or for whom capecitabine is an acceptable treatment option, were enrolled. A standard 3+3 design was used to assess escalating doses of CB-839 (400-800 mg) and capecitabine (500-1000 mg/m2) in four dose levels. CB-839 was given orally twice daily continuously and capecitabine was given orally twice daily on days 14/21 of a 21-day treatment cycle. Dose-limiting toxicity period was 21 days. Restaging CT scans were obtained every 9 weeks with response assessment per RECIST. Adverse events were assessed per CTCAEv4. Sixteen patients were enrolled, with 7 patients being treated at the final dose level (CB-839 800 mg and capecitabine 1000 mg/m2). No dose-limiting toxicity was observed. Ten patients achieved stable disease as their best response with 9 being fluoropyrimidine resistant. Among the 16 patients, 12 were CRC patients who were 5-FU resistant. Consistent with our preclinical data, the median progress-free survival (PFS) of seven PIK3CA mutant CRC patients was 26 weeks, whereas the median PFS of five PIK3CA WT CRC patients was 16 weeks. Notably, the PFS of three PIK3CA mutant CRC patients was over six months (8, 9 and 13 months, respectively). A phase II trial of the drug combination in metastatic PIK3CA mutant CRC patients is ongoing. In summary, our preclinical and clinical studies suggest that targeting glutamine metabolism may be a promising approach to treat CRCs with PIK3CA mutations. This abstract is also being presented as Poster A06. Citation Format: Jennifer Eads, Yiqing Zhao, David Bajor, Zhenghe John Wang. Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR09.

Phase Ib trial combining rapid determination of drug-drug interaction (DDI) followed by a dose finding period to assess safety and preliminary efficacy of fimepinostat plus venetoclax in patients with aggressive B-cell lymphoma.

8056 Background: Fimepinostat (F), a dual inhibitor of PI3K (α, β, δ) and HDACs type 1/2, causes suppression of MYC levels (Shulman et al., 2017). A pooled analysis of diffuse large B-cell lymphoma (DLBCL) pts treated with F in two Ph 1/2 trials revealed an objective response rate in evaluable/ITT MYC-altered DLBCL pts of 29%/23%, respectively (Landsburg et al., 2018). Based on compelling preclinical activity of F in combination with venetoclax (V) (a Bcl2 inhibitor), we initiated a Ph 1b/2 study of F + V in pts with relapsed or refractory (R/R) DLBCL or high-grade B-cell lymphoma (HGBL), with or without MYC alteration. V is metabolized primarily by CYP3A, and preclinical studies showed that F may inhibit CYP3A4 (IC50 of 13.58 and 0.28 µM for midazolam and testosterone, respectively), suggesting F could cause DDI with V. Methods: Cohorts of patients received increasing dose levels of F administered on a 5-days-on/2-days-off (5/2) schedule in combination with daily V in 21-day cycles (Cohort 1: F 30 mg QD 5/2 + V 400 mg QD; Cohort 2: F 60 mg QD, 5/2 + V 400 mg QD; Cohort 3: F 60 mg QD 5/2 + V 800 mg QD). A potential DDI was assessed during Cycle 0 (Table), where PK for V (10 mg) monotherapy was compared to that for V (10 mg) in the presence of F. Patient PK samples were collected, analyzed and reviewed in < 10 days to determine the final ramp-up dose level of V. Results: As of 1-Feb-2020, 16 pts have been enrolled in 2 dose cohorts. Intensive PK analysis of 13 pts showed only mild (≤ 2-fold) to no increase in V exposure in the presence of F. In Cohort 1 (n = 6), the mean AUC increased 1.6-fold, and mean Cmax by 1.5-fold. In Cohort 2 (n = 7), no increase in mean AUC (0.9-fold) or Cmax (1.0-fold) was observed. Accordingly, all pts ramped up V to 100% of the target dose (400 mg) upon entering Cycle 1; rapid escalation of V was well tolerated. DLT was observed in 1 pt (Grade 3 diarrhea) in Cohort 2. Overall, 75% of TEAEs have been mild or moderate (Grade 1/2), and most were of limited duration. 11 pts (69%) experienced SAEs; 4 pts (25%) had SAEs considered related to either F or V. Conclusions: Real-time PK evaluation showed that F had only a mild to no DDI with V. F + V is well tolerated at clinically active dose levels, and evaluation of higher dose-level cohorts was ongoing. Enrollment in Cohort 2 remains on-going. Clinical trial information: NCT01742988 . [Table: see text]

Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Abstract LB-294: Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. As a metabolite, glutamine is first converted to glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers including 20 to 30% of colorectal cancer (CRC). We found that oncogenic PIK3CA mutations render CRCs addicted to glutamine through an upregulation of glutamate pyruvate transaminase 2 (GPT2), thereby facilitating conversion of glutamate to α-KG. Here, we report that CB-839, a potent GLS inhibitor developed by Calithera Biosciences, inhibits xenograft tumor growth of PIK3CA mutant, but not WT, colorectal cancers. Remarkably, combination of CB-839 with 5-fluorouracil (5-FU) induces regression of xenograft tumors in four different PIK3CA mutant CRC models. These exciting preclinical data prompted us to perform a Phase I and Phase II clinical trial to assess combination of CB-839 with capecitabine, an oral prodrug of 5-FU. For the Phase I trial, patients with advanced solid tumors and disease progression on standard treatment, or for whom capecitabine is an acceptable treatment option, were enrolled. A standard 3+3 design was used to assess escalating doses of CB-839 (400-800 mg) and capecitabine (500-1000 mg/m2) in four dose levels. CB-839 was given orally twice daily continuously and capecitabine was given orally twice daily on days 14/21 of a 21 day treatment cycle. Dose-limiting toxicity period was 21 days. Restaging CT scans were obtained every 9 weeks with response assessment per RECIST. Adverse events were assessed per CTCAEv4. Sixteen patients were enrolled with 7 patients being treated at the final dose level (CB-839 800 mg and Capecitabine 1000 mg/m2). No dose-limiting toxicity were observed. Ten patients achieved stable disease as their best response with 9 being fluoropyrimidine resistant. Among the 16 patients, 12 were CRC patients who were 5-FU resistant. Consistent with our preclinical data, the median progress-free survival (PFS) of seven PIK3CA mutant CRC patients was 25 weeks, whereas the median PFS of five PIK3CA WT CRC patients was 16 weeks. Notably, the PFS of three PIK3CA mutant CRC patients was over six months (8, 9 and 13 months respectively). A Phase II trial of the drug combination in metastatic PIK3CA mutant CRC patients is ongoing. In summary, our preclinical and clinical studies suggest that targeting glutamine metabolism may be a promising approach to treat CRCs with PIK3CA mutations. Citation Format: Yiqing Zhao, Jennifer Eads, David Bajor, zhenghe wang. Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-294.

Abstract OT3-06-01: Phase Ib clinical trial of coPANlisib in combination with Trastuzumab emtansine (T-DM1) in pre-treated unresectable locally advanced or metastatic HER2-positive breAst cancer (BC) “PANTHERA”-CTRIAL-IE 17-13

Abstract Background:The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrant activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor administered i.v. with low nanomolar activity against both PI3Kα and PI3Kβ. Copanlisib has been shown to re-sensitise trastuzumab resistant cell lines to trastuzumab with synergism seen in some cell lines between copanlisib and HER2 targeted therapy. Trial design: This is a phase Ib open label, single arm adaptive, multi-centre trial of copanlisib in combination with T-DM1. Eligible patients will receive T-DM1 at 3.6mg/kg i.v. on day 1 of a 21-day cycle plus copanlisib. Copanlisib will be administered i.v. according to the dose escalation scheme (dose level 1 is 45mg on days 1 and 8, dose level 2 is 60mg on days 1 and 8, dose level 3 is 60mg on days 1, 8, and 15). Dose level -1 will be 45 mg on day 1 in case dose de-escalation is needed. We will enrol 3 to 6 patients per dose level. All patients in each level must have completed at least the first cycle of therapy before enrolment in the next dose level. Patients not completing the first cycle for a reason other than toxicity will be replaced. Dose escalation and determination of the Maximum Tolerated Dose (MTD) will be based on the occurrence of Dose Limiting Toxicities (DLT). Eligibility criteria:Eligible patients are those with unresectable locally advanced or metastatic HER2-positive BC who previously received trastuzumab and a taxane, separately or in combination. Participants must have adequate organ function and ECOG PS ≤ 2 Objectives:The primary objective is to determine the MTD for copanlisib in combination with T-DM1 in patients with pre-treated unresectable locally advanced or metastatic HER2-positive BC. Secondary objectives include evaluating the safety, efficacy and cardiotoxicity in patients treated with this regimen. Exploratory objectives include examining for predictive biomarkers in tumour tissue and blood or plasma and to examine molecular tumour adaptation to clinical trial therapy. Statistical methods: Patients will be accrued in cohorts of 3 patients according to a standard 3+3 algorithm, with dose escalation and determination of MTD based on the occurrence of DLT, using the usual threshold probability of 33%. The final dose level will be expanded to include a total of 6 additional patients (expansion cohort). Present accrual and target accrual:The trial will start accrual in October 2018. Maximum of 24 patients will be enrolled. Citation Format: Hassan A, Gullo G, O'Reilly S, Ruiz-Borrego M, Toomey S, Grogan L, Breathnach O, Morris PG, Walshe JM, Crown J, O'Mahony D, Falcon A, Egan K, Hernando A, Teiserskiene A, Kelly CM, Coate L, Hennessy BT. Phase Ib clinical trial of coPANlisib in combination with Trastuzumab emtansine (T-DM1) in pre-treated unresectable locally advanced or metastatic HER2-positive breAst cancer (BC) “PANTHERA”-CTRIAL-IE 17-13 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-06-01.

Phase I Trial of Concurrent Stereotactic Body Radiation Therapy and Nelfinavir for Locally Advanced Borderline or Unresectable Pancreatic Cancer-Final Results

The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiation therapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes. Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received 3 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received SBRT(5 fractions)/NFV. Dose escalation was as follows: 1) 25 Gy/625 mg BID × 3 wk; 2) 25 Gy/1250 mg BID × 3 wk; 3)30 Gy/1250 mg BID × 3 wk; 4) 35 Gy/1250 mg BID × 3 wk; 5) 35 Gy/1250 mg BID × 5wk; and 6) 40 Gy/1250 mg BID × 5 wk. Pancreaticoduodenectomy was performed thereafter if deemed resectable; if not, gemcitabine/leucovorin/fluorouracil was administered. Forty-six patients enrolled (10/2008-5/2013). Thirty-nine patients received SBRT/NFV on protocol; 16 (41%) experienced any grade ≥2 adverse event (AEs) during and 1 month after SBRT. There were 21, 11, and 2 instances of grades 2, 3, and 4 toxicities, respectively. Four instances of grade 3 events & both grade 4 events occurred in a single patient (started prior to SBRT/NFV) at the initial dose level. The final dose level was the maximum tolerated dose. Long-term follow up revealed that 5 patients had late gastrointestinal (GI) bleed (2, superior mesenteric artery pseudoaneurysm; 1, unknown; 1, negative esophagogastroduodenoscopy; 1, disease progression invading GI). The median overall survival was 14.4 months. Six (15%) patients experienced a local failure; the median local failure-free survival was not reached. Twenty-six had a distant failure as the first failure site (9, liver; 6, lung; 9, peritoneum). The median distant failure-free survival was 11 months, and the median all failure-free survival was 10 months. Twelve patients underwent pancreaticoduodenectomy; their median survival (19 months) was similar to those of unresected patients receiving 35-40 Gy (18 months) (p=0.924). As compared to those receiving 25-30 Gy (10 months), there was a trend towards higher survival in whom 35-40 Gy was delivered (p=0.083). Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally-advanced pancreatic cancer is safe and yields encouraging outcomes; a phase II study is currently ongoing. A close attention to SBRT plan & delivery is warranted to decrease the risk of late GI bleed.

Short Course, Two Day Accelerated Hypofractionated Partial Breast Balloon Brachytherapy: A Phase II Multi-Institutional Trial

Accelerated partial breast irradiation (APBI) is presently an option for post lumpectomy treatment in properly selected women. When using brachytherapy to deliver treatment, conventionally the target volume is treated to 34 Gy in 10 fractions delivered BID over 5 days. A company sponsored prospective non-randomized trial was initiated to evaluate brachytherapy based dose-escalation to further reduce the overall treatment time to 2-3 days, improving the patient experience. This study reports the local control and toxicity results of the multi-institutional trial. Patients presenting with ductal carcinoma in situ and/or invasive disease, size ≤3cm, ER or PR positive, resected with margins free of tumor and axillary node negative were eligible. Patients were treated using a multi-lumen single entry balloon device placed post lumpectomy with ultra sound guidance. The intent of the trial design was to treat 30 patients (pts) at a dose level of 7 Gy x 4 fractions (fx), 30 pts at a dose level of 8.25 Gy X 3 fx and 30 pts at a dose level of 9.5 Gy x 2 fx. All fractions were separated by at least 6 hours and delivered over 2 days. End points evaluated included in-breast disease control, toxicity rates and physician reported cosmetic outcome. Fisher’s exact two-sided probability was used. Thirty patients were enrolled and evaluable on the first dose level, 29 pts on the second dose level and the trial was closed prior to enrollment on the final dose level due to lack of sponsorship. Four institutions participated. Median age was 64 years old. Mean tumor size was 1.3 cm (±0.9 cm) with invasive ductal carcinoma in 67.8%, invasive lobular carcinoma in 8.5% and DCIS in 23.7%. All tumors were estrogen receptor positive. The most common location of these tumors was upper outer quadrant (50.9%). Balloon diameter of 4-5cm was used in 73.2% of pts and a larger balloon, 5-6 cm, in 26.8%. Median follow up time was 51 months (range 21-86 months). In-breast failures were reported in five pts (8.5%), one considered true recurrence and four considered elsewhere. There was no difference in local control recurrence based on dose level. A trend towards less toxicity in pain and seroma (p= 0.02 and 0.04) with the second dose level is appreciated but low event rates preclude conclusions. There were no statistically significant differences in terms of fibrosis, hyperpigmentation, and fat necrosis between the two dose levels. Overall good/excellent cosmetic outcome was reported in 95% of patient (n=55) with no difference seen between dose levels. Results from this prospective phase II trial suggest extreme hypo-fractionation of dose with delivery over 2 days for early stage breast cancer appears safe with acceptable toxicity, cosmetic outcome and in-breast control rates. This experience generates support for a larger trial opening opportunities for treatment time reduction and improvement in the patient experience.

Mibefradil dihydrochoride with hypofractionated radiation for recurrent glioblastoma: A phase I dose expansion trial.

e14046 Background: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options. We performed a high-throughput screen for DNA repair inhibitors and identified mibefradil dihydrochloride, a T-type calcium channel blocker. We and others revealed that mibefradil acts as a glioma radiosensitizer. Recent studies in our laboratory indicate that mibefradil blocks non-homologous end joining. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and radiation therapy (RT), in a Phase I recurrent GBM study. Methods: The Primary objective was to determine mibefradil MTD with concurrent hypofractionated RT. Secondary objectives included safety, pharmacokinetics, progression-free survival (PFS) and overall survival (OS). A tertiary objective included assessing intra-tumoral drug concentrations. In this novel translational sub-study, patients were given mibefradil for 5 days prior to surgery, followed by a re-resection. Resected tissues were analyzed for the presence of drug in situ. Inclusion criteria included histologically proven GBM progressive following RT and temozolomide. Patients received mibefradil, dose escalated from 150mg/day using a 3 + 3 design. RT consisted of 5 fractions of 600 cGy each, delivered over 2 weeks. Results: Nineteen patients enrolled from 9/2014 - 12/2016. There were 4 DLTs; a final dose level of 200 mg/day was reached. Median PFS and OS were 3 months and 9 months, respectively. Four patients (22%) achieved a PFS interval of ≥4 months (longest 8 months). One patient had a complete radiographic response. Intriguingly, mibefradil was detected at micromolar levels in GBM tumor tissue in 2 patients enrolled in the translational sub-study. We detected drug levels in biopsies from T1-post contrast and FLAIR regions on MRI and these levels correlate with that required for tumor cell radiosensitization in vitro. Conclusions: Our data suggest mibefradil can be safely co-administered with RT over a 17 day period at 200 mg/day. Promising local control signals apparent in a selection of patients, and we have demonstrated that pharmacologically effective concentrations of the drug are achieved in resected brain tumor tissue. Clinical trial information: NCT02202993.

Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors

SummaryBackground Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1–28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses. Dose limiting toxicities (DLTs) were only assessed during the first cycle of treatment and response evaluation was performed every 2 cycles. The effects of tanibirumab on several angiogenic factors were analyzed. Results From October 2011 to September 2013, a total of 26 patients with refractory solid tumors were enrolled. The median age was 58 years (range, 27–75) and 20 patients were male. The most common tumor type was colorectal cancer (N = 19) and seven patients had a history of previous bevacizumab treatment. As hemangioma continued to occur, the final dose level, 28 mg/kg, was not performed. DLTs were not found, and the MTD was confirmed to be 24 mg/kg. Hemangioma was observed in 16 patients (61.5%), but all were grade 1–2 and disappeared after discontinuation of the study drug. Among the 18 patients in the efficacy set, no objective response was observed, but 11 patients showed stable disease. PKs were characterized by dose-dependent linear exposure and the mean trough concentrations exceeded biologically relevant target levels at 12 mg/kg and above. Serum VEGF, soluble VEGFR-2, and PlGF increased at the 4 mg/kg dose level and above. Conclusions Treatment with tanibirumab showed a tolerable toxicity profile and modest clinical efficacy in patients with refractory solid tumors. A phase II trial of tanibirumab is ongoing now.

Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy.

7009Background: Venetoclax (VEN) is a potent, orally bioavailable BCL-2 inhibitor with single-agent activity in relapsed/refractory acute myeloid leukemia (AML) patients (pts), displaying synergistic activity with hypomethylating agents in preclinical studies. This trial evaluates VEN plus decitabine (DEC) or azacitidine (AZA) in treatment (Tx)-naive AML pts ≥ 65 y (NCT02203773). Methods: Tx-naive pts (ECOG PS ≤ 2, ≥ 65 y, intermediate- or poor-risk karyotype) not eligible for standard induction therapy received DEC (Arm A: 20 mg/m2 iv) daily on days (D) 1−5 or AZA (Arm B: 75 mg/m2; subcutaneous or iv) daily on D 1−7 of each 28-D cycle in combination with once-daily continuous oral VEN. VEN dose escalation follows a 3+3 design; 1200 mg is the final dose level. Objectives include safety, preliminary efficacy, and biomarker evaluations. Results: As of 11/28/15, 39 pts (49% male; median age 74 y [65–85 y]) have been enrolled in Arm A (n = 20) and Arm B (n = 19). Median time on study is111 D (6−375 D); 16 pts...

A Phase I Study of BKM120 (Buparlisib) and Rituximab in Patients with Relapsed or Refractory B-Cell Non-Hodgkins Lymphoma (NHL)

Introduction: BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Several PI3K inhibitors have single agent activity in relapsed or refractory B-cell NHL. We are conducting a phase I trial of the combination of BKM120 and rituximab to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), tolerability and preliminary efficacy in patients with relapsed or refractory NHL. Methods: Patients ≥ 18 years with relapsed or refractory B-cell NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/waldenstrom's macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), and activated B cell subtype diffuse large B cell lymphoma (ABC DLBCL) who have received at least one prior therapy were eligible. Additional eligibility included ECOG Performance Status 0-2, adequate renal and liver function, absolute neutrophil count (ANC) ≥ 750/mm3, platelets ≥ 50,000/mm3, INR ≤ 2.0, and fasting glucose < 120 mg/dL. Prior autologous or allogeneic transplant was allowed if patient did not require immunosuppressive therapy for GVHD. Prior treatment with a pan-selective PI3K inhibitor was not allowed but prior therapy with a selective PI3K inhibitor, Bruton's tyrosine kinase inhibitor or other B-cell receptor targeting agent was allowed. Patients with active moderate or severe major mood or psychiatric disorders were excluded given mood-associated toxicities. Treatment consisted of escalating doses of BKM120 (mg/day) days 1-28 and standard rituximab dosing at 375 mg/m2 days 2, 8, 15, and 22 of cycle 1 and then day 1 of cycles 3, 5, 7, 9, 11 for 28-day cycles. A standard 3+3 dose escalation schema was followed. DLT was defined during cycle 1 and included: treatment delays > 28 days for toxicity; grade 5 toxicity: grade 3 febrile neutropenia > 7 days; grade 4 febrile neutropenia or infection; grade 3 or 4 somnolence, cognitive changes, altered mood, anxiety, or confusion; grade 2 somnolence, cognitive changes, altered mood, anxiety, or confusion that does not resolve to ≤ grade 1 within 14 days; other grade 3 or 4 non-hematologic toxicity with the exception of grade 3 nausea, vomiting, diarrhea, or electrolyte abnormalities that are reversible within 72 hours of holding treatment. Patients without toxicity were allowed to continue treatment until disease progression. To further evaluate safety, preliminary efficacy and correlatives, an expansion cohort of an additional 12 patients to be treated at the MTD was planned, 6 patients with indolent NHL or MCL and 6 patients with ABC DLBCL. Response was assessed by CT or PET/CT after cycles 2, 4, 6, and then every 3 months while on therapy. Results: From August 2014 until July 2015, seven patients were enrolled in this trial. The median age was 67 (range 52-71). Histologies included FL (n=5) and MZL (n=2). Three patients were treated at dose level (DL) 1 (BKM120 80 mg/day). No DLT's occurred. Four patients have been treated at DL2 (BKM120 100 mg/day). One patient experienced a DLT consisting of grade 3 maculopapular rash. The rash occurred cycle 1 day 15 and resolved with interruption of therapy which was continued on day 22 at a reduced dose of BKM120 at 80 mg without any recurrence. The rash was confounded by the simultaneous initiation of allopurinol. Grade 3 toxicities occurred in 2/7 (29%) patients, including grade 3 maculopapular rash in one patient (DLT) and grade 3 hyperglycemia in one patient. Patients have received a median 3 cycles of therapy to date (range 1-9) and six remain on therapy. At DL1, two patients with FL achieved a partial response (PR). At DL2, one patient with FL achieved a PR. Overall response rate for the 5 evaluable patients is 60%. The other two evaluable patients had best response of stable disease. One patient discontinued study to pursue alternative therapy. Conclusions: Combined therapy with the pan-PI3 kinase inhibitor BKM and rituximab in patients with relapsed or refractory B-NHL has been well tolerated, with only one DLT of maculopapular rash that resolved with therapy interruption and did not recur at a lower dose. Patients continue to enroll at the current and final dose level of BKM120 mg administered at 100 mg daily with standard rituximab dosing, with a planned expansion cohort at the MTD. While the number of patients treated has been small, preliminary efficacy has been observed including all enrolled FL patients assessable for response achieving a PR. Disclosures Maddocks: Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Cohen:BMS, Janssen: Research Funding; Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy. Christian:Seattle Genetics: Consultancy, Research Funding; Novartis: Other: IDSM; Celgene: Consultancy; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding. Blum:Janssen: Research Funding; Pharmacyclics: Research Funding; cephalon: Research Funding; Celgene: Research Funding.

HARMONY: An Open-Label, Multicenter, 2-Arm, Dose-Finding, Phase 1b Study of the Combination of Ruxolitinib and Buparlisib (BKM120) in Patients with Myelofibrosis (MF)

BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated improvements in splenomegaly, MF-related symptoms, and quality of life measures and prolonged survival in 2 phase 3 studies. JAK signaling can activate the PI3K/mTOR pathway, and constitutive PI3K activation has been implicated in numerous cancers. Preclinical and early clinical results indicate benefit with inhibition of PI3K in MF. Buparlisib is a pan-PI3K inhibitor with specific and potent activity against class I PI3Ks. The aims of HARMONY are to evaluate the safety of co-administration of RUX and buparlisib in patients (pts) with MF and determine a recommended phase 2 dose (RP2D).METHODS: This is a dose-finding, phase 1b study (NCT01730248) of RUX plus buparlisib in intermediate- or high-risk MF pts. Pts must have palpable splenomegaly ≥ 5 cm below the costal margin and MF symptoms. There are 2 treatment groups (JAK inhibitor–naive pts [arm A] and pts not benefiting from prior JAK inhibition [arm B]) and 2 study phases (dose escalation and expansion). Dose escalation is guided by a Bayesian logistic regression model with overdose control and depends on dose-limiting toxicities in cycle 1 and other safety findings. Each dose level consists of ≥ 3 evaluable pts; the 5 dose levels are (RUX [mg bid]/buparlisib [mg qd]) 10/60, 15/60, 15/80, 20/80, 20/100. 9 evaluable pts are required at the final dose level to determine an RP2D and proceed to the expansion phase; 10 additional pts per arm will be treated at the RP2D. PK of RUX was assessed by LC-MS/MS on day 1 after the first dose of RUX and on days 2 and 8 when administered in combination with buparlisib.RESULTS: To date, 33 pts (arm A, n = 20; arm B, n = 13) have been treated in the dose-escalation phase. Baseline characteristics were (arm A and arm B) median age, 64 y (range, 48-79 y; 45% ≥ 65 y) and 61 y (53-74 y; 31% ≥ 65 y); male, 50% and 62%. RP2D was selected based on tolerability in the investigated dose levels, with additional confirmation from dose-selection recommendations derived through a Bayesian model.Currently, RUX 15 mg bid/buparlisib 60 mg qd was determined as the RP2D in both arms; the study is proceeding into the expansion phase.At data cutoff (April 1, 2014), 15 (75%) and 8 (62%) pts were ongoing in arm A and arm B with a median exposure of 11.3 wk (range, 2.3-48.4 wk) and 19.0 wk (range, 0.6-50.9 wk), respectively. The primary reasons for discontinuation included lack of efficacy (10%) in arm A and AEs (15%) in arm B; all other reasons were in 1 pt each. There was 1 death (arm A) from duodenal ulcers/perforation, assessed as not related to study drugs by the investigator.Despite the short follow-up, a ≥ 50% reduction from baseline in palpable spleen length was achieved by 70% and 54% of pts in arms A and B; 7 pts had a resolution of splenomegaly (6 in arm A; 1 in arm B). All pts with prior JAK inhibitor treatment, including 5 who had no previous spleen length reductions, had reductions with the combination.Hematologic AEs included anemia (all grade [grade 3/4]: arm A, 30% [15%]; arm B, 31% [23%]) and thrombocytopenia (40% [10%]; 62% [39%]). Nonhematologic AEs were primarily grade 1/2 (Table). Overall, 20% and 23% of pts experienced serious AEs; these occurred in 1 pt each, with the exception of pyrexia (n = 2).PK parameters of RUX were comparable when administered alone or in combination with buparlisib, suggesting a lack of impact of buparlisib on RUX PK.CONCLUSIONS: The combination of RUX and buparlisib was well tolerated, with early signs indicating promising efficacy even in pts who have previously failed JAKi; preliminary RP2D was assessed as RUX 15 mg bid/buparlisib 60 mg qd for both arms. Updated efficacy and safety for the dose-escalation phase will be presented (July 1, 2014 data cutoff).TableNonhematologic AEs in ≥ 2 Pts in Either ArmPts, %Arm A n = 20Arm B n = 13All GradeGrade 3/4All GradeGrade 3/4Abdominal distension15080Abdominal pain100150Abdominal pain lower00150Abdominal pain upper50150Diarrhea100468Dyspepsia10000Nausea100310Stomatitis15588Vomiting50150Asthenia00310Fatigue100230General health deterioration00150Edema peripheral10000Pyrexia1502315Nasopharyngitis150150Decreased appetite50468Hyperglycemia15500Hyperkalemia55150Arthralgia20580Pain in extremity10080Dizziness50230Anxiety205150Confusional state10080Depressed mood00158Depression00158Insomnia50150Epistaxis50150Hyperhidrosis00310Night sweats00230Hypertension10500 DisclosuresDurrant:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Yes; Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Buparlisib is an investigational agent. Koren-Michowitz:Novartis: Honoraria, Research Funding. Lavie:Novartis: Membership on an entity’s Board of Directors or advisory committees. Martinez-Lopez:Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Stalbovskaya:Novartis: Employment, Equity Ownership. Atienza:Novartis: Employment. Iommazzo:Novartis: Employment. Gopalakrishna:Novartis: Employment. Gisslinger:AOP ORPHA: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

Abstract P5-14-04: Preoperative single-fraction partial breast radiotherapy – Initial results from a novel phase I dose-escalation protocol with exploration of radiation response biomarkers

Abstract Purpose/Objectives(s): Women with biologically favorable early stage breast cancer are increasingly treated with accelerated partial breast techniques. However, many alternative techniques require costly specialized equipment not routinely available in most radiation oncology facilities. In addition, suboptimal cosmetic outcomes have been reported with the external beam technique, possibly related to large post-operative treatment volumes. To address these issues, we designed a phase I dose-escalation protocol to determine the maximally tolerated dose (MTD) of a single radiosurgery treatment delivered preoperatively to the intact tumor plus a small margin. Materials/Methods: Women aged 55 or older with clinically node negative, ER and/or PR+, HER2-, T1 invasive carcinomas were enrolled (n = 26). Patients with low/intermediate grade in situ disease <2cm were also included (n = 6). Breast MRI was required for target volume delineation. An intensity-modulated treatment plan was designed to deliver 15, 18, or 21Gy in a single fraction. An additional breast MRI, including T1-weighted, T2-weighted, diffusion-weighted and dynamic-contrast enhanced imaging, was obtained prior to lumpectomy which took place within 10 days of radiation treatment. Acute toxicity was assessed 3-4 weeks after radiation and any grade 3/4 toxicity possibly, probably, or definitely related to treatment was considered dose limiting. Tumor tissue was obtained from diagnostic and lumpectomy specimens. Immunohistochemistry (IHC) for Fas was performed on paraffin-embedded samples before and after radiation. A histoscore was created using the average membrane and cytoplasmic staining intensity multiplied by the percentage of positive cells. Results: Thirty-two women were treated, 8 each at the 15, 18, and 21Gy dose levels with an additional expansion cohort at the final 21Gy dose level. The maximally tolerated dose was not reached. Three patients required post-operative conventional radiation due to high-risk tumor features (ex. larger primary, nodal involvement). At a median follow-up of 6.8 months, primarily mild toxicities (grade 1-2 dermatitis, fibrosis, and pain) were noted. At 6 months (n = 20), all reported cosmetic outcomes are excellent or good. At 12 months (n = 10), 80% are excellent or good. Both patients with a fair/poor cosmetic outcome received radiosurgery plus post-operative conventional treatment; one experienced grade 3 breast atrophy. There have been no local or distant recurrences to date. Post-treatment MRIs were obtained in 20/32 patients, with early indicators of decreased cell density and increased vascular permeability. Sixteen patients had evaluable paired IHC and six demonstrated significant Fas up-regulation after radiation. The mean combined post-treatment histoscore was about twice as high as the mean pre-treatment score. Conclusion: Preoperative stereotactic radiotherapy to the intact breast tumor can be delivered with widely available clinical tools in a convenient single fraction, and provides a unique opportunity to study breast cancer radiation response. 21Gy did not yield dose-limiting toxicity and will be utilized for future studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-04.

Abstract B83: Phase I trial of panobinostat and fractionated stereotactic radiation therapy for recurrent glioma.

Abstract Introduction: Panobinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitivity effect. This is an interim report of the phase I study to evaluate the safety and tolerability of panobinostat combined with fractionated stereotactic radiation therapy (FSRT) for patients with recurrent glioma. Methods: This is a phase I trial with 3+3 design. Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was 30-35 Gy delivered in 10 daily fractions. Panobionostat was administrated by mouth, once daily, every Monday, Wednesday, and Friday with radiation treatment. Panobionostat was escalated from 10 to 30 mg. Results: Fifteen patients were enrolled in the trial. Four patients were excluded from the analysis. One patient had tumor progression prior to initiation of treatment, and didn't receive panobinostat. Three patients didn't finish protocol treatment due to increase in QTc exceeding the protocol limit due to panobinostat toxicity. There was no treatment related grade 3 or higher toxicities in the 10 mg and 20 mg dose levels. Four patients were enrolled in the final dose level, 30 mg. One developed grade 3 leukopenia, and grade 4 low ANC (absolute neutrophil count). The hematological toxicities were possibly related to the treatment. Two more patients are required to compete the final dose level and determine the maximum tolerated dose of panobionostat when combined with FSRT in patients with recurrent glioma. Median follow up for living patient is six months. Median progression free survival, and overall survival have not been reached. Conclusions: Panobinostat administrated with FSRT is well tolerated to the dose of 20 mg. The tolerability of 30 mg dose level is still under evaluation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B83. Citation Format: Wenyin Shi, Yaacov R. Lawrence, Maria Werner-Wasik, David Andrews, Voichita Bar Ad, James Evans, Yaron Moshel, Christopher Farrell, Kevin Judy, Jon Glass, Lyndon Kim, Adam P. Dicker. Phase I trial of panobinostat and fractionated stereotactic radiation therapy for recurrent glioma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B83.

Phase I Study of Aurora Kinase Inhibitor MLN8237 and Bortezomib in Relapsed or Refractory Multiple Myeloma

AbstractAbstract 1859Genome wide RNA interference studies identified Aurora Kinase (AURK) A and B as lethal targets in Multiple Myeloma (MM) while suppression of these genes also sensitized MM to bortezomib (BTZ). MLN8237 is an oral inhibitor of AURKA. We therefore conducted a Phase I clinical trial of MLN8237 in combination with BTZ. The study enrolled a total of 19 patients at 5 institutions. 9 patients are still receiving active treatment as of the date of this report. Study Design:The phase I portion of this study uses a standard 3+3 design to determine the maximum tolerated dose (MTD) of MLN8237 and BTZ in patients with relapsed/refractory MM. Eligibility required a minimum of 1 and maximum of 4 lines of prior therapy. Patients who have received prior BTZ therapy were allowed on trial as long as they did not progress during prior BTZ or ≤ 60 days of therapy discontinuation.The following laboratory values were required £7 days prior to registration. ANC3 1000/mL, Hgb ≥9 g/dl, PLT3 100,000/mL, Total bilirubin £1.5 × upper limit of normal (ULN), Creatinine £ 2.5 × ULN, a baseline LVEF ≥45%. Patients were required to be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration. Treatment Overview:The first 3 patients received MLN8237 at 25 mg po days 1–14 and BTZ at 1.3 mg/m2/dose iv. days 1, 4, 8, 11 on a 28 day schedule. Based on data from other concurrent trials an amendment changed dosing of MLN8237 to 20, 30, 40 or 50 mg po twice daily on days 1–7 and BTZ was given at 1.5mg/m2 iv weekly on a 28 day schedule. Results:Median age of patients was 64, 63% were male, 31% had high risk genetics, 84% had prior stem cell transplant, 53% of patients were relapsed and 47% were relapsed and refractory to therapy. No DLTs were observed even at the highest dose level tested. However, one patient at the highest dose level required a platelet transfusion in order to initiate treatment on time in Cycle 2. Thus, a further 3 patients accrued at the highest dose level before declaring the MTD and proceeding to phase II. The highest dose level (Dose Level 3: MLN8237 50 mg po twice daily on days 1–7; BTZ 1.5 mg/m2 iv. given on days 1, 8, 15, 22) was the final dose level tested (the MTD of single agent MLN8237 is 50mg as defined in other Phase I trials). The ORR was 26% (1 CR, 4 PR); when minor responses are included the ORR was 52%. Median follow up was 4.3 months (range 0.9–23.4) and PFS was 5.5 months. At last follow up 12 patients showed no progression and 7 had progressed. Toxicity:63% of patients experienced a grade 3AE and 5% a grade 4 AE. Grade 3 or 4 toxicity seen in more than one patient was all hematologic with thrombocytopenia and neutropenia being common. Other toxicity of any grade regardless of attribution occurring in more than 20% of patients included neuropathy 63%, fatigue 63%, diarrhea 53%, nausea 47%,vomiting 26%, infection 32%, alopecia 21%, Conclusions:The MTD of the combination is MLN8237 50 mg po twice daily on days 1–7 and BTZ at 1.5mg/m2 iv weekly. Phase II testing is underway and updated results will be presented. Disclosures:Stewart:Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Vij:Millennium: Speakers Bureau. Hofmeister:Celgene: Advisory board Other, Honoraria.

Lenalidomide Plus Melphalan Without Prednisone for Previously Untreated Older Patients With Multiple Myeloma: A Phase II Trial

We conducted a phase II trial that evaluated the tolerability and efficacy of combining lenalidomide with melphalan in previously untreated patients with multiple myeloma who were not candidates for autologous stem cell transplantation. After a run-in phase of 6 patients, we planned to conduct a randomized phase II selection-design trial that assessed 2 dose levels of lenalidomide, given days 1 to 21, combined with melphalan, given days 1 to 4, and every 28 days. Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). Coprimary endpoints were the frequency of dose-limiting Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). toxicities (DLT) and complete response (CR). Four patients received M9L10; all experienced DLTs, which resulted in closure of this cohort. When using the same schedule, we then sequentially tested M6L10 (melphalan 6 mg/m(2) on days 1 to 4 and lenalidomide 10 mg/d on days 1 to 21 every 28 days) (6 patients), M4L15 (melphalan 4 mg/m(2) on days 1 to 4 and lenalidomide 15 mg/d on days 1 to 21 every 28 days) (6 patients), and M5L10 (melphalan 5 mg/m(2) days 1 to 4 and lenalidomide 10 mg/d days 1 to 21 every 28 days) (34 patients). In each cohort, the DLT endpoint was reached because of severe and prolonged hematologic toxicity. At the final dose level, M5L10, 20 of 27 patients experienced DLTs within their first 3 cycles; among 10 patients who received at least 6 cycles, none achieved a CR. Combining lenalidomide plus melphalan without prednisone is associated with substantial hematologic toxicity that precludes cyclical administration of adequate drug doses.