Dose-limiting Hematologic Toxicity Research Articles

Safety of Palbociclib in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoma: A Children's Oncology Group Pilot Study

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children's Oncology Group (COG) AINV18P1 trial are reported. Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population. Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing. Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial. Disclosures Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey:La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris:Merck: Other: Travel funding. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.

Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

A Phase 2 Trial of Inotuzumab Ozogamicin (InO) in Children and Young Adults with Relapsed or Refractory (R/R) CD22+ B-Acute Lymphoblastic Leukemia (B-ALL): Results from Children's Oncology Group Protocol AALL1621

A Phase 2 Trial of Inotuzumab Ozogamicin (InO) in Children and Young Adults with Relapsed or Refractory (R/R) CD22+ B-Acute Lymphoblastic Leukemia (B-ALL): Results from Children's Oncology Group Protocol AALL1621

Effective Dosing of Topotecan with Carboplatin in Relapsed Ovarian Cancer

Patients and Methods: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5.Results: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule.Conclusion: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.TAJ 2016; 29(2): 31-36

Molecular Patterns of Response and Outcome in the Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT study)

▪Background: Venetoclax (VEN) is a potent small molecule BH3-mimetic drug that selectively targets the prosurvival protein BCL-2 and has an emerging role for treatment in Acute Myeloid Leukaemia (AML). This ongoing Phase 1b study aims to evaluate the optimal dose, safety and efficacy of VEN in combination with modified intensive chemotherapy in fit, elderly patients with AML who have not received prior induction chemotherapy. Here we present updated data including molecular correlates of response and treatment outcomes.Methods:Eligibility: Patients were enrolled with AML (excluding APL), age ≥65 years (≥60 years if monosomal karyotype), ECOG 0-1 and adequate organ function. Prior HMA/LDAC was permitted after a 14-day washout. Treatment: 1) Dose escalation cohorts comprised VEN 50mg (Cohort A), 100mg (B), 200mg (C), 400mg (D) or 600mg (E); 2) a 7-day VEN pre-phase incorporating dose ramp-up to minimise tumour lysis risk followed by a 7-day overlap with chemotherapy (day -6 to +7); 3) attenuated induction chemotherapy with cytarabine 100mg/m2/day IVI d1-5 staggered with idarubicin 12mg/m2 IV d2-3. For patients in remission, 4 cycles of consolidation were administered, comprising 14 days of VEN (day -7 to +7) with bolus cytarabine (100mg/m2/day IV d+1-2) and idarubicin (12mg/m2 IV d+1) followed by 7 cycles of VEN monotherapy maintenance; planned to commence q28d. Antifungal azoles were avoided during VEN exposure. The first patient was enrolled 17JUL2016. Molecular studies- Next generation sequencing using a 54-gene TruSight myeloid panel was performed on baseline bone marrow samples. FLT3-ITD testing was performed by capillary electrophoresis. RT-qPCR was used to detect minimal residual disease (MRD) in NPM1-mutated cases (assay sensitivity: 10-5-10-6).Results: The data cut-off date was 13JUL2018. 44 patients were enrolled with 3 patients still in the induction cycle. Median age was 72 years (range 63-80 years; 23% ≥75 years), 66% of patients were male, 41% had secondary AML and 38% prior hypomethylating agent (HMA) exposure. Main grade ≥3 non-haematological adverse events during induction were febrile neutropenia (56%), sepsis (32%), rapid atrial fibrillation (15%), diarrhoea (12%), nausea (10%) and localised infection (10%). No clinical TLS was observed. One hematologic dose-limiting toxicity was reported in cohort E (VEN 600mg), but a maximum tolerated dose has not been reached. We observed progressive delay in platelet count recovery as patients proceeded with each cycle of therapy (median time to platelets ≥50x109/L was 25d in induction, 37d in consolidation 1 and 57d in consolidation 4). Treatment-related mortality was 7% in induction. 18/38 (47%) had ≥30% relative reduction in bone marrow (BM) blasts after 7 days of pre-phase VEN monotherapy, with no correlation between VEN dosage and the degree of BM blast reduction.Overall CR/CRi rate was 71%. CR/CRi was achieved in 95% of patients with de novo AML (vs 42% in secondary/therapy-related AML). Response rates were 88% in intermediate vs 46% in adverse cytogenetic risk AML. Responses in patients with prior HMA therapy were 43% and 84% for previously untreated patients. Molecular data were available for 41 patients. 98% had ≥1 mutation detected. (Figure 1) Responses in response-evaluable patients were most common in NPM1 mutant AML (100%; n=7), followed by RUNX1 (90%; n=11), RAS (90%; n=10) and IDH (89%; n=9). Lowest responses were observed in TP53 mutant AML (33%; n=9). NPM1 MRD assessment was performed on 6 patients, of which 5 (83%) achieved NPM1 MRD negativity. (Figure 2) Updated response, response duration and survival data will be presented, along with molecular characteristics of relapse.Conclusion: To date, VEN up to 600mg in combination with 5+2 induction chemotherapy is tolerable in fit elderly patients with AML. Initial response rates >80% were observed in de novo AML, as well as NPM1, RUNX1, RAS and IDH mutant AML, whereas responses were lower in patients with prior HMA exposure, adverse karyotype, secondary and TP53 mutant AML. Molecular determinants of relapse require further study. [Display omitted] DisclosuresWei:Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Amgen: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Fong:Celgene: Other: Advisory board; Novartis: Other: Advisory board; Amgen: Research Funding; Pfizer: Other: Speaker fees. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Roberts:Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax.

Development of Thrombocytopenia and Survival Outcomes in Newly Diagnosed Multiple Myeloma

Introduction: Thrombocytopenia is a major dose-limiting hematologic toxicity of anti-myeloma therapy. Clinical trial data in the relapsed/refractory setting have linked the development of thrombocytopenia during therapy with bortezomib with improved response to treatment. Less is known about the prognostic significance of early treatment related thrombocytopenia during initial therapy for newly diagnosed multiple myeloma (MM) using novel agents.Aims: The aim of this study was to characterize the effect of new, treatment related thrombocytopenia during initial therapy for newly diagnosed MM with novel agents on survival and clinical response.Methods: We identified 690 patients with newly diagnosed MM treated at Mayo Clinic, Rochester from January 2004 to December 2015 through a retrospective record review. All patients received novel agents including proteasome inhibitors (PI) and/or immunomodulatory drugs, were evaluable using the International Myeloma Working Group uniform response criteria, and had platelet counts greater than 150,000/µL prior to initial treatment. Survival outcomes and response were compared in patients who became thrombocytopenic within two cycles of first line treatment, defined as a nadir platelet count less than 150,000/µL, and in patients who did not develop thrombocytopenia. Survival estimates were calculated using the Kaplan-Meier method, and the log-rank test was used to compare survival in subgroups. Multivariable-adjusted proportional hazards regression models were fit to adjust for known prognostic factors including age, sex, International Staging System (ISS) stage, and the presence of cytogenetic high-risk abnormalities. Logistic regression was performed to evaluate for differences in response between groups. P-values less than 0.05 were considered statistically significant.Results: Of the 690 patients treated with novel agents, 495 patients (72%) received a PI as initial therapy. Median follow up was 3 years (0.1-13.2), median overall survival (OS) was 6.6 years (95% CI 5.9-8.0), and median progression free survival (PFS) was 4.84 years (95% CI 3.53-8.98). 123 patients (18%) developed thrombocytopenia within two cycles of first line therapy; two patients developed platelet counts less than 20,000/µL and none developed counts less than 10,000/µL. Differences in survival estimates for OS and PFS for patients who did not develop thrombocytopenia and those who became thrombocytopenic are illustrated in Figure 1. Median OS in patients who did not develop thrombocytopenia was 7.4 years (95% CI 5.9-8.9), compared to 4.6 years (95% CI 4.1-6.0) in those who became thrombocytopenic (p = 0.003), while median PFS was 5.4 years (95% CI 3.63-NR) and 3.53 years (95% CI 0.49-NR), respectively (p = 0.008). Similar results for both OS and PFS were observed when using a platelet nadir of less than 100,000/µL. These relationships remained statistically significant when adjusting for the effect of known prognostic factors including age, sex, ISS stage, and high-risk cytogenetics, for both OS and PFS (HR = 1.70, 95% CI 1.12-1.59, p = 0.013, n = 387 and HR = 1.56, 95% CI 1.03-2.37, p = 0.036, n = 387, respectively). Multivariable-adjusted estimates were similar for the subset of patients receiving PI containing regimens. Development of thrombocytopenia within two cycles was not associated with very good partial response or better (VGPR+) (p = 0.588) or with complete response (CR) (p = 0.968). This was also true for the subset of patients receiving PIs (p = 0.827 and p = 0.772, respectively).Conclusions: Our results suggest that the development of new, treatment related thrombocytopenia within two cycles of first-line therapy with novel agents is independently associated with inferior survival in newly diagnosed MM. This was also true in the subset of patients receiving PI containing regimens. In contrast to prior studies, there was no association between early treatment-related thrombocytopenia and response to treatment for either novel agents in general or PI based therapies.Figure 1: Kaplan-Meier progression free and overall survival estimates stratified by platelet count ≥ 150,000/µL (no thrombocytopenia) and <150,000/µL (new thrombocytopenia) within two cycles of initial therapy with novel agents. [Display omitted] DisclosuresLacy:Celgene: Research Funding. Gertz:Prothena: Honoraria; Teva: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Physicians Education Resource: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; annexon: Consultancy; celgene: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Once weekly paclitaxel associated with a fixed dose of oral metronomic cyclophosphamide: a dose-finding phase 1 trial

BackgroundThe primary aim of this trial was to determine the recommended phase II dose (RP2D) of weekly paclitaxel (wP) administered in combination with oral metronomic cyclophosphamide (OMC).MethodsPatients ≥ 18 years of age with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50 mg twice a day). A 3 + 3 design was used for dose escalation of wP (40 to 75 mg/m2) followed by an expansion cohort at RP2D. Dose-limiting toxicity (DLT) was defined over the first 28-day cycle as grade ≥ 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) or any toxicity leading to a dose reduction.ResultsIn total, 28 pts. (18 in dose-escalation phase and 10 in expansion cohort) were included, and 16/18 pts. enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts. (hematological toxicity) at doses of 40, 60, 70 and 75 mg/m2 of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 patients in the expansion phase had a hematological DLT. At RP2D (n = 14), the maximal grade of drug-related adverse event was Gr1 in three patients, Gr2 in six patients, Gr3 in one patient and Gr4 in one patient (no AE in three patients). At RP2D, a partial response was observed in one patient with lung adenocarcinoma.ConclusionThe combination of OMC and wP resulted in an acceptable safety profile, warranting further clinical evaluation.Trial registrationTRN: NCT01374620; date of registration: 16 June 2011.

P2.01-058 Pharmacokinetic Parameter Variability of Docetaxel between Individuals and Its Relationship with Hematological Toxicity

Docetaxel is the commonly used chemotherapy drugs of various types of tumors. However, the major adverse effect of which is the dose-limiting hematologic toxicity. In clinical practice, 3/4 grade neutropenia and febrile (FN) is the severe side effects threatening the patient life. This research aims to analyze the variability of docetaxel’s medicine area under the curve (AUC) between individuals and its relationship with hematological toxicity in advanced NSCLC, which sets up the mathematical model to predict its hematological toxicity by docetaxel AUC to lay the theoretical foundation for individual adjustment in future. Select 32 patients with advanced NSCLC in Shandong Cancer Hospital that receiving docetaxel chemotherapy treatment from 2014-10 to 2015-12. Adopt Mycare® reagent kit to determine the blood concentration, and calculate the docetaxel AUC over model software of non-mixed effects. After standardized treatment, analyze the AUC variability between individuals, relationship of AUC with decreased amount of neutrophils before or after the chemotherapy, and the relationship of AUC with 3/4 grade neutropenia. And make the fitting with different methods to set up the mathematical model in relationship with decreased percentage of neutrophils after AUC prediction chemotherapy and incidence rate of 3/4 grade neutropenia. 1. The AUC of 32 patients in the first cycle after standardized treatment that use docetaxel is between 1.8ug.h/ml-4.7ug.h/ml in average of 3.32±0.12ug.h/ml. The difference between the maximum value and minimum one is 2.6 times. 2. AUC value has the tendency that increases as cycle number increases. However, the number of chemotherapy cycle has no statistical significance of AUC influence (F=0.186, P=0.824). 3. The model predicting the decreased percentage of neutrophils with docetaxel AUC is : y1 = 1.4812x2 + 3.0217x + 29.061 (cycle 1), y2 = 4.3981x2 + 14.006x + 50.532 (cycle 2), y3 = 2.0683x2 + 2.1257x + 19.604(cycle 3), y4 = 4.683x2 - 19.273 + 61.398 (cycle 4); The model predicting the incidence rate of 3/4 grade neutrophils is y=19.383ln(x)+2.4005. (x=AUC). This research sets up the mathematical model to predict the decreased percentage of neutrophils and incidence rate of 3/4 grade neutropenia by docetaxel AUC, which provides basis for screening high-risk patients who may suffer seriously hematological toxicity and lay the theoretical foundation for individualized adjustment based on doxetaxel AUC. In addition, as the first cycle of doxetaxel AUC has important reference value, it suggests that all patients receiving docetaxel chemotherapy at the first time must receive AUC test.

Abstract 4042: N-121, a novel polypeptide conjugate of SN-38, demonstrated enhanced intratumoral accumulation and sustained release of free SN-38 with potent antitumor activity

Abstract Introduction: SN-38 is a critical chemotherapeutic agent active against a variety of solid tumors including advanced colorectal cancer. Clinical use of SN-38 is hampered by its poor solubility in pharmaceutically acceptable solvents. Although irinotecan, the only approved prodrug of SN-38, is widely used, its efficacy is limited by low conversion to the active SN-38 as well as hematologic and gastrointestinal dose-limiting toxicities. In an attempt to improve the water solubility, antitumor activity and safety profiles of SN-38, we synthesized a water soluble polypeptide-SN-38 conjugate (N-121) and examined its antitumor activity and pharmacokinetics (PK) in mouse models. Methods: Antitumor activity and PK of SN-38, administered as N-121 or irinotecan, was evaluated following tail vein injection in male nude mice with subcutaneous orthotopic xenografts of the HCT116 human colon cancer. Mice received N-121 400 mgk (mg/kg) (32 mkg of eq. SN-38) or irinotecan 80 mgk once a week for 2 weeks and were followed for up to 46 days. Results: N-121 drastically improved by over 1000 fold the water solubility of SN-38. At a SN-38 equivalent dose of less than half of that of irinotecan, N-121 resulted in a much longer tumor growth delay (36 days) than irinotecan (14 days). The more durable tumor growth inhibition with N-121 was consistent with its enhanced intratumoral accumulation: intratumoral trough levels of SN-38 were about 250-fold higher than those observed in plasma, compared with only 15-fold with irinotecan. With N-121, Intratumoral levels of SN-38 remained stable over the PK observation period (48 h), contrasting to a marked decline in SN-38 levels with irinotecan; intratumoral trough levels of SN-38 from N-121 were about 50-fold higher than those achieved with irinotecan. N-121 was well tolerated with a slight weight loss of 7.2%. Conclusion: N-121, a novel water soluble polypeptide-SN-38 conjugate, exhibited enhanced and sustained intratumoral exposure of SN-38 with high antitumor activity in a mouse xenograft tumor model. These promising results warrant further evaluation of N-121. Note: This abstract was not presented at the meeting. Citation Format: Haojun Wang, Wei Li, Xiaojian Zhou, Liuyi Wan, Guanghui Wen. N-121, a novel polypeptide conjugate of SN-38, demonstrated enhanced intratumoral accumulation and sustained release of free SN-38 with potent antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4042. doi:10.1158/1538-7445.AM2017-4042

Paclitaxel once weekly (wP) combined with fixed dose of oral metronomic cyclophosphamide (OMC): A dose-escalating phase I trial.

e14015 Background: OMC, as continuous administration of low doses of chemotherapy acts as direct cytotoxic as well as antiangiogenetic agent. wP also induces antiangiogenic effects in mouse models. The aims of this trial were to determine the recommended Phase 2 dose (RP2D) of wP given in combination with OMC, and estimate activity and safety of the combination. Methods: Methods This is a single-center, phase 1 trial. Patients (pts) &gt; 18 years with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50mg x2/day). A 3+3 design was used for Dose-Escalation of wP (40 mg/m² to 75 mg/m²), followed by an expansion cohort at RP2D. The primary endpoint was the dose-limiting toxicity (DLT), defined as grade &gt; 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) occurring in the first 28 days, or any toxicity leading to a dose reduction. Results: 28 pts (18 in dose-escalation phase and 10 in expansion cohort) were included between May 2011 and December 2013. The sex ratio was 2:1, the median age was 54.5 (range, 26-67); the most common primary tumors were colorectal cancers (n = 9), sarcomas (n = 4), Head &amp; Neck (n = 3). 16/18 pts enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts (hematological toxicity) at dose 40, 60, 70 and 75 mg/m² of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 pts in the expansion phase had an hematological DLT. At RP2D (n = 14), the maximal grade of adverse events (AE), regardless of causality, was Gr2 in 3 pts, Gr3 in 7 pts, Gr4 in 3 pts and Gr5 in 1 pt; the maximal grade of treatment-related AE was Gr1 in 1 pt, Gr2 in 8 pts, Gr3 in 3 pts and Gr4 in 1 pt (no AE in 1 pt). At RP2D, the median PFS was 2.8 mo and Growth Modulation index was ≥1.33 in 4/14 pts (29%). There was 1 objective response (1/14; 7%): 1 pt with lung adenocarcinoma achieved a partial response. Conclusions: The combination of OMC and wP resulted in an acceptable safety profile. Further evaluation of this combination with wP at 70mg/m² could be warranted in a phase 2 trial. Clinical trial information: NCT01374620.

Pilot Study of Decitabine and Vorinostat with Chemotherapy for Relapsed ALL: A Report from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium

Acquired drug resistance is a major reason for relapse and death in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of acquired drug resistance is a potential solution. DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have been shown to reverse drug resistance gene signatures and restore chemosensitivity in relapsed ALL. We report results investigating decitabine (DNMTi) (10-15 mg/m2/dose) and vorinostat (HDACi) (180 mg/m2/dose) with vincristine, dexamethasone, mitoxantrone and PEG-asparaginase (UKALL R3 backbone) for relapsed/refractory ALL. Twenty-three patients with refractory or ≥2nd relapse B-ALL were enrolled (Table 1). Median age was 12 (range, 1-21) years. Toxicity was graded according to CTCAE v4.0. The most common grade (Gr) 3-4 toxicities included hypokalemia (65%), anemia (61%), febrile neutropenia (57%), hypophosphatemia (43%), hyperbilirubinemia (39%), thrombocytopenia (39%), neutropenia (35%), sepsis (30%), lung infection (30%) and infection/infestations-other (30%). Non-hematologic dose limiting toxicity (DLT) was defined as any Gr 3 or 4 adverse event that was at least possibly attributed to decitabine and/or vorinostat with the exception of nausea (Gr 3), vomiting (Gr 3), transaminase elevation that returned to Gr ≤1 or baseline prior to the end of the course, fatigue, fever/infection, electrolyte abnormalities that were transient and not associated with clinical sequelae, albumin, alkaline phosphatase, GGT and anorexia. Hematologic DLT was defined as an absence of peripheral blood count recovery within 6 weeks of starting chemotherapy. Any patient who experienced a DLT after receiving at least 1 dose of decitabine or vorinostat was evaluable for DLT. Patients who did not experience a DLT had to receive a pre-determined amount of protocol therapy as outlined in the study to be evaluable for DLT. Seventeen of 23 patients were evaluable for DLT. Three patients experienced DLTs as follows: Gr 3 cholestasis, Gr 3 steatosis, Gr 4 hyperbilirubinemia (n=1); Gr 4 seizure, Gr 4 somnolence, Gr 3 delirium (n=1); and Gr 3 pneumonitis, Gr 3 hypoxia, Gr 3 hyperbilirubinemia (n=1). The study was suspended and amended after the first 5 patients enrolled (decitabine, 15mg/m2), due to significant infectious toxicities [4 of 5 patients reporting invasive fungal infections: C. kruseii (n=2), C. lusitaniae (n=1), and C. guillermondii (n=1)] and two DLTs (reported above). The treatment schema was modified to lower the dose of decitabine (10mg/m2/dose) and to reduce the duration from days 1-7/15-21 to 1-5/15-19. The duration of vorinostat was also reduced from days 3-10/17-24 to 2-7/16-21 (Figure 1). In addition, anti-fungal prophylaxis with either an echinocandin or amphotericin agent was required. Despite these dose modifications, infectious complications remained common with 17/23 (74%) patients reporting Gr ≥3 infections including invasive fungal disease in 35% (8/23). In analyzing all 23 patients, the complete response rate (CR + CR with incomplete blood count recovery) was 39% (9/23). Fourteen patients (61%) were able to complete full protocol therapy and evaluable for response. The remaining 9 patients did not complete therapy, primarily due to treatment-related toxicities, and were not evaluable. Nine of the 14 patients (64%) achieved a complete response with the remaining 5 reporting stable disease (36%). Minimal residual disease (MRD) testing via flow cytometry was performed on 7 of 9 patients who achieved a CR with a median level of 0.087% MRD (range, 0.00% to 1.6%) detected. Overall survival at 6 months was 35.1% (95% CI, 16.0 - 54.9) and 23.4% (95% CI, 7.8 - 43.6) at 1-year. Death was reported in 18/23 (78%) patients at a median of 10 weeks from study start (range, 3-138). Cause of death was attributed to refractory leukemia (n=8), treatment related toxicity (n=5), infection (n=3) and transplant-related toxicity (n=2). Despite encouraging response rates including low MRD, the combination of decitabine and vorinostat with intensive chemotherapy in this patient population was determined not to be feasible. A future follow-up study with a less intensive chemotherapy backbone is needed to determine if these two promising epigenetic agents can be successfully incorporated into the treatment of pediatric ALL. This study is registered at http://www.clinicaltrials.gov as NCT01483690. [Display omitted] [Display omitted] DisclosuresWayne:Kite Pharma: Honoraria, Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.

177lu-Satetraxetan-Lilotomab in the Treatment of Patients with Indolent Non-Hodgkin B-Cell Lymphoma (NHL), Phase 1/2 Safety and Efficacy Data from Four Different Pre-Dosing Regimens

177Lu-Satetraxetan-lilotomab (Betalutin®) is a novel CD37-binding IgG1 antibody labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of Non-Hodgkins lymphoma. CD37 is an internalizing transmembrane antigen highly expressed on most B-cell malignancies, and is a promising therapeutic target. The optimisation of the pre-dosing regimen prior to administration of 177Lu-Satetraxetan-lilotomab may result in an improved safety and efficacy profile. The phase 1 stage of this study is designed with 4 arms to test different pre-dosing regimens (no pre-dosing, rituximab and two doses of lilotomab) on the effect of 177Lu-Satetraxetan-lilotomab.Methods:Patients with relapsed incurable NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study.All patients received pre-treatment with rituximab (375 mg/m2) to deplete peripheral B cells and improve biodistribution of the labelled antibody. Pre-dosing with lilotomab (cold anti-CD37 antibody) was given in arms 1 and 4 or rituximab in arm 3, within 4 hours of 177Lu-Satetraxetan-lilotomab to block binding in the non-tumour tissue. The pre-treatment and pre-dosing regimen used in each arm is summarised below:Arm 1: rituximab day1 and 8, lilotomab (40 mg) plus Betalutin day 29Arm 2: rituximab day 1 and 8, Betalutin day 29Arm 3: rituximab day 1, rituximab plus Betalutin day 15Arm 4: rituximab day 1, lilotomab (100 mg/m2) plus Betalutin day 15The starting dose for Arm 1 was10 MBq/kg and was 15 MBq/kg for arm 2, 3 and 4 and in phase 2. Response was assessed by FDG PET/CT scans at 3 and 6 months post-treatment and then by CT scan up to 5 years after treatment. The results of the protocol specified interim analysis will be presented.Results:A total of36 patients have been enrolled into study, of which 24 are currently evaluable. Patients enrolled into the study had either follicular (n=20), mantel cell (n=2) or marginal zone (n=2) lymphoma. The number of prior therapies ranged from 1 to 8. The efficacy and safety results from patients enrolled into Arms 3 and 4 and treated with two different pre-dosing regimens will be presented for the first time.The most common toxicities observed were hematologic with all dose limiting toxicities (DLTs) being reversible and manageable and related to thrombocytopenia and neutropenia. At a dose of 15 MBq/kg, pre-dosing with 40 mg of lilotomab (Arm 1 and phase 2) reduced the incidence of hematological DLTs to 14% (2/14 patients) compared with 100% (2/2 patients) with no pre-dosing in Arm 2.No DLTs have been reported at 10 MBq/kg in either Arm 1 or 2. Fourteen serious adverse events (SAEs) were reported by 8 patients: Atrial fibrillation (n=2) and platelet count decreased (n=2) were the only SAEs reported by more than one patient. There have been no deaths and no secondary malignancies or other long-term safety events.The overall tumor response rate observed in 23 patients evaluable for efficacy was 57%, comprising 7/23 complete responses, 6/23 partial responses, 5/23 stable disease and 5/23 with progressive disease. In addition, one patient had a confirmed transformed lymphoma at 3 months. One patient is still in remission more than 3 years after treatment and two further patients are still in remission more than 2 years after treatment.Conclusions: Betalutin has the potential to be a novel, safe and effective therapy for B-cell malignancies with durable responses. Betalutin, a single dose, ready-to-use formulation, has a predictable and manageable safety profile which is improved by pre-dosing. Most AEs were haematological, all transient and reversible. DisclosuresKolstad:Nordic Nanovector: Other: Membership of Scientific Advisory Board. Illidge:Nordic Nanovector: Consultancy. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Baylor Curtis:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment. Turner:Nordic Nanovector: Employment. Hartvig Larsen:Nordic nanovector: Equity Ownership. Holte:Mundipharma: Research Funding; Amgen: Research Funding.

Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort

ObjectiveThis phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance.MethodsForty-six patients with advanced solid tumours refractory to treatment received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 625 and 780 mg/m2.ResultsOverall, IT-139 was well tolerated. The treatment-emergent adverse events (AEs) occurring in ≥20% of patients were nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had AEs that were ≤grade 2, regardless of relationship with the study drug. Of the total 38 efficacy-evaluable patients, one patient with a carcinoid tumour achieved a durable partial response. Nine additional patients achieved stable disease . The MTD was determined to be 625 mg/m2. IT-139 exhibited first-order linear pharmacokinetics.ConclusionsIT-139 demonstrated a manageable safety profile at the MTD and modest anti-tumour activity in this study of patients with solid tumours refractory to treatment. The lack of dose-limiting haematological toxicity and the absence of neurotoxicity position IT-139 well for use in combination with a broad spectrum of anticancer drugs.Trial registration numberNCT01415297.

A Phase I Study of Idarubicin Dose Escalation for Remission Induction Therapy in Acute Myeloid Leukemia

The maximum tolerated dose (MTD) of idarubicin has been acknowledged to be 12-15 mg/m2/day for 3 days for acute leukemias. Its MTD should be reevaluated in the treatment of acute myeloid leukemia (AML) in the era of granulocyte colony-stimulating factor and better supportive care. We conducted a phase I study to investigate the safety of escalating doses of idarubicin in combination with cytarabine 100 mg/m2/day for 7 days for previously untreated AML. The starting dose of idarubicin was 12 mg/m2/day for 3 days with dose escalations by 3 mg/m2/day. Cohorts of three patients were treated at each dose level, and the idarubicin dose was escalated up to 18 mg/m2/day until at least two patients among a cohort of three to six patients experienced the dose-limiting toxicities (DLTs) (traditional 3+3 design for phase I clinical trials: J Natl Cancer Inst 2009;101:708). Hematologic DLTs were defined as the time to recovery of neutrophils {absolute neutrophil count (ANC) ≥500/μL} or platelets (platelet count ≥20,000/μL) exceeded 42 days after the start of induction therapy (J Clin Oncol 2004;22:4290). Non-hematologic DLTs were defined as grade 4 or 5 toxicities (Leukemia 1998;12:865). We adopted the NCI CTCAE v3.0 to grade the hematologic and non-hematologic toxicities. Thirteen adult patients were enrolled in the study, but two and two were excluded at level 1 and level 2, respectively, because they received reinduction therapy for resistant disease within 4 weeks after the start of the assigned induction therapy. Consequently, nine patients were evaluable for the phase I study. The median times to recovery of neutrophils (ANC ≥500/μL) after the start of induction therapy at level 1, level 2, and level 3 were day 20 (range, 19-22), day 19 (range, 17-20), and day 25 (range, 21-26), respectively. The median times to recovery of platelet (platelet count ≥20,000/μL) at each level were day 20 (range, 19-23), day 20 (range, 16-34), and day 24 (range, 20-35), respectively. Therefore, grade 4 hematologic toxicities were observed at all 3 levels; however, these hematologic toxicities did not meet the criteria of the hematologic DLTs as defined in this study. There was any instance of grade 4 non-hematologic toxicity at each dose level. No death associated with the induction treatment was observed in this trial. Hematologic and non-hematologic DLTs as defined above were not observed at all 3 dose levels; therefore, idarubicin 18 mg/m2/day for 3 days could be defined as the MTD for this trial. DisclosuresNo relevant conflicts of interest to declare.

Abstract C2: Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study

Abstract Background: Resistance to apoptosis is a typical hallmark of cancer. Inhibitor of Apoptosis Proteins (IAPs) block caspase activation, modulate NF-kB signaling pathways, and are involved in resistance to standard chemo and radiation therapies. As such, IAPs antagonism represents an attractive target for therapeutic intervention. Debio 1143 is a potent orally-available monovalent SMAC mimetic antagonist of IAPs currently in clinical development. A previous phase I study showed Debio 1143 was well tolerated up to 900 mg QD as a single agent, with strong evidence of pharmacodynamic (PD) activity and appropriate pharmacokinetic (PK) disposition at doses ≥ 120 mg. [1] This Phase I study defined the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, PK, and PD of Debio 1143 in combination with carboplatin and paclitaxel. Methods: Treatment-naïve and previously treated patients with squamous non-small cell lung cancer (NSCLC), and previously treated patients with triple negative breast cancer (TNBC) and platinum-resistant epithelial ovarian cancer (EOC) were treated with carboplatin (AUC 6) and paclitaxel 175 mg/m2 on day 1 of every 21-day-cycle up to a maximum of 6 cycles, combined with escalating doses of Debio 1143, administered once daily on days 1-5 of every 21-day cycle. The starting dose of Debio 1143 was 200 mg QD. Results: Thirty-one patients were included in the study. Four patients are still on treatment. Hematological DLTs were observed in 2/4 patients in the first two dose levels despite the reduction of Debio 1143 dose to 100 mg. PK data suggested a PK interaction between Debio 1143 and paclitaxel. The study protocol was amended to reduce the doses of carboplatin to AUC 5 and paclitaxel to 135 mg/m2. Afterwards, patients received Debio 1143 doses of 100 mg (n = 2), 125 mg (n = 2), 175 mg (n = 2), 200 mg (n = 7), 225 mg (n = 5), 250 mg (n = 9). DLTs were febrile neutropenia (n = 2) and G3 ALT increase (n = 1). The MTD of Debio 1143 to be combined with carboplatin (AUC 5) and paclitaxel (135 mg/m2) is 250 mg QD. Most common treatment-related AEs reported in ≥ 15% of patients were asthenia (n = 13), decreased appetite (n = 11), diarrhea (n = 9), neutropenia (n = 9), thrombocytopenia (n = 8), anemia (n = 8), nausea (n = 7), fatigue (n = 7), vomiting (n = 4), AST increase (n = 4), hypomagnesaemia (n = 4), myalgia (n = 4),and epistaxis (n = 4). Paclitaxel exposure in patients dosed at 135 mg/m2 in combination with Debio 1143 was similar to historical control dosed at 175 mg/m2 due to a 25 to 40% reduction in clearance. Preliminary evaluation of PD endpoints confirmed Debio 1143-induced cIAP1 degradation in PBMCs at doses starting from 100mg. In line with the expected mechanism of action, modulation of serum PD markers of NF-kB signaling pathways and epithelial apoptosis was also observed during treatment. Twenty-three patients were evaluable for response. Partial responses by RECIST have been observed in 7 patients with EOC (6/17) and TNBC (1/5). Conclusions: The combination of Debio 1143 with carboplatin and paclitaxel is well tolerated, with significant PD activity and hints of activity. The clinical PK interaction between Debio 1143 and paclitaxel is well-controlled and managed in the patients. These findings support a further Phase II program. [1] HI Hurwitz et al., Cancer Chemother Pharmacol (2015) 75:851 Citation Format: Isabelle Ray-Coquard, Christophe Le Tourneau, Nicolas Isambert, Carlos A. Gomez-Roca, Philippe Cassier, Marie Paule Sablin, Bruno Gavillet, Daniela Purcea, Elisabeth Rouits, Claudia Schusterbauer, Claudio Zanna, Pierre Fumoleau, Jean-Pierre Delord. Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C2.

Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis

The tumor suppressor p53 is thought to play a role in megakaryocyte (MK) development. To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production. This drug has been previously been evaluated in clinical trials of cancer patients where thrombocytopenia was one of the major dose-limiting toxicities. In this study, we demonstrated that administration of RG7112 in vivo in rats and monkeys results in thrombocytopenia. In addition, we identified two distinct mechanisms by which RG7112-mediated activation of p53 affected human megakaryocytopoiesis and platelet production in vitro. RG7112 promoted apoptosis of MK progenitor cells, resulting in a reduction of their numbers and RG7112 affected mature MK by blocking DNA synthesis during endomitosis and impairing platelet production. Together, the disruption of these events provides an explanation for RG7112-induced thrombocytopenia and insight into the role of the p53-MDM2 auto-regulatory loop in normal megakaryocytopoiesis.

Maintenance Therapy With Decitabine After Allogeneic Hematopoietic Stem Cell Transplantation For Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Introduction Disease recurrence is the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after alloHSCT. Decitabine (DAC) is a hypomethylating agent that irreversibly binds to and inhibits DNA methyltransferase-1, leading to loss of DNA methylation. DAC maintenance may help eradicate minimal residual disease and facilitate a graft-versus-leukemia effect. Lower DAC doses are expected to be better tolerated after alloHSCT and equally effective in promoting hypomethylation. Additionally, DAC maintenance may have a favorable effect on the incidence of GVHD by enhancing the effect of T-regulatory lymphocytes (Choi et al, Blood, 2012). Methods Patients (pts) with AML/MDS in complete remission (CR) after alloHSCT, with ANC&gt; 1,500/mm3, platelets&gt; 50,000/mm3, and without grade III-IV acute GVHD were eligible to receive DAC, starting between day +50 and +100 after alloHSCT. We investigated 4 DAC doses: 5, 7.5, 10 and 15 mg/m2/day IV x 5 days of a 6-week cycle, for a total of 8 cycles. Each cohort contained 4-8 evaluable patients. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which&lt; 20% of patients experience hematologic or non-hematologic dose limiting toxicities (DLT) during the 1st cycle of treatment. GVHD prophylaxis was at the physician discretion. Results 19 pts were enrolled to date; the median age was 60 y (22-66); 14 pts had AML and 5 MDS. All conditioning regimens were myeloablative; 14 donors were unrelated and 5 related. 3 cohorts have been completed and a final 4th cohort is currently enrolling. Median follow-up from alloHSCT is 24 mo (7-36). 8 pts (44%) completed all 8 cycles: 7 pts remain in CR with stable counts and full donor chimerism and 1 pt developed CNS-only relapse 26 mo after alloHSCT. 9 pts went off study before cycle 6: 1 pt for poor compliance after 6 cycles, 3 pts for relapsed disease (after 1, 2 and 5 cycles, respectively), 2 pts for sepsis, and 2 pts after physician decision. 6 pts have died: 3 from relapse, 2 from sepsis after 3 cycles of DAC (they were not neutropenic at a time), and 1 form sepsis &gt;1 y after getting off study. 2 pts are still on study passed 3rd cycle. DAC maintenance was well tolerated. Associated hematological toxicities were mostly grade I/II leukopenia and thrombocytopenia. There was one occurrence of hematological DLT. No MTD has been reached. Non-hematological toxicities were grade I/II nausea, fatigue, neuropathy, and transaminase elevation. 2 pts had grade I-II acute GVHD prior to starting DAC and both resolved while on DAC; 1 pt developed grade IV gut GVHD coinciding with first cycle of DAC that completely resolved on DAC; 1 pt developed late acute GVHD of skin and liver around 6th cycle of DAC that resolved after few wks. 2/8 pts who completed 8 cycles of DAC developed very mild skin and oral chronic GVHD not requiring any systemic therapy, 1/8 pt developed late acute GVHD responding to therapy, and 1 pt developed overlap GVHD syndrome. 4/7 pts who went off study prior cycle 6, and did not have an early relapse, developed severe chronic GVHD requiring intensive immunosuppressive therapy. Conclusion To our knowledge this is the first report of DAC as maintenance therapy after alloHSCT. DAC at the dose of 15 mg/m2 for 5 days every 6 weeks is safe and can be administered in heavily pretreated pts in the post-alloHSCT setting. Approximately 43% of pts were able to receive all 8 cycles. The lack of toxicities and low incidence of GVHD indicate that a longer period of administration should be investigated. Although there is a trend of increased FOXP3 expression, results were not statistically significant. Further correlative studies, including genome-wide methylation studies, are ongoing. Disclosures: Off Label Use: Decitabine maintenance after alloHSCT.

Abstract C295: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Abstract Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50&amp;lt;1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. PARP inhibition has also been shown to be effective in preclinical models of small cell lung cancer and Ewing sarcoma, possibly related to high PARP expression. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES). Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 µg/d with 1000 µg/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC's was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively. Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet. Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway. Clinicaltrial.gov ID: NCT01286987 BRCA Breast and Ovarian CancerNBRCA Tumor TypeResponse18BreastCRPRSD &amp;gt; 12 weeksCBR*18Breast1 (6%)9 (50%)∧14 (78%)Response - 25 RECIST evaluable; 27 CA-125 evaluable28Ovarian28OvarianCRPRCA-1251 (4%)10 (40%)19 (70%)2PancreasCRPRSD ≥ 12 weeks2Pancreas0 (0%)0 (0%)2 (100%)**∧3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C295. Citation Format: Zev A. Wainberg, Johann S. de Bono, Lida Mina, Jasgit Sachdev, Lauren Averett Byers, Rashmi Chugh, Charlie Zhang, Joshua W. Henshaw, Andrew Dorr, John Glaspy, Ramesh Ramanathan. Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. [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 C295.

Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction

We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer. We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m(2) day 1, 8 and oral capecitabine 650 mg/m(2) b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ≤15 μmol/L] and 3 cohorts with increasing TB (16-39, 40-80, >80 μmol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography-tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis. Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10(-3)) and capecitabine (p = 10(-5)), and low intracellular gemcitabine triphosphate concentrations (p = 10(-3)). Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine's activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.

Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.