Experienced Dose-limiting Toxicity Research Articles

Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours

BackgroundPreclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab. MethodsTemsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150–250 mg/m2, until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation. ResultsAmong 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m2 and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration. ConclusionsCombination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development.

Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer.

The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. Patients with unresectable or inoperable stage II/III NSCLC with ECOG≤1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]≅76 Gy/38), 20.0 Gy/7 (EQD2≅84 Gy/42), and 22.7 Gy/7 (EQD2≅92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which ≥30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted.

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases

We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3mg/kg every 3weeks, starting on day 3 of WBRT or 2days after SRS. The ipilimumab dose was escalated to 10mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3mg/kg (n=7) or 10mg/kg (n=9). The median follow-up was 8months (arm A) and 10.5months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5months and 8months and in arm B was 2.1months and not reached, respectively. Concurrent ipilimumab 10mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

Phase I study of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) in limited-disease small cell lung cancer (LD-SCLC).

e20023 Background: Amrubicin and cisplatin is one of active regimens for patients with extensive-disease small cell lung cancer (ED-SCLC). Combined modality of combination chemotherapy and concurrent thoracic radiotherapy has been recognized as standard treatment for LD-SCLC. This study aimed to determine the maximum tolerated dose (MTD), and dose limiting toxicity (DLT) of amrubicin and cisplatin with concurrent TRT in LD-SCLC. Methods: Patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naïve, PS0-1, age = < 75, LD-SCLC, and adequate organ function. Patients received escalating doses of amrubicin on days 1, 2, and 3, under a fixed 60 mg/m2 of cisplatin on day 1. Four cycles of chemotherapy were repeated every 4 weeks. TRT of once-daily 2Gy/day commenced on day 2 of the first cycle of chemotherapy. The initial doses of amrubicin was 20 mg/m2, and the dose was escalated to 25 and 30 mg/m2. Results: Eight patients (male/female = 3/5; PS 0/1 = 4/4; median age (range) = 68.5 (60-73)) were enrolled at three dose levels. Three patients in 20 mg/m2 and three patients in 25 mg/m2 dose levels did not experienced DLT. Two of two patients in 30 mg/m2 dose level experienced DLTs. The presentation of DLTs included grade4 neutropenia and leukopenia lasting more than four days. Evaluation of responses were 7 partial response and 1 progressive disease (response rate 87.5%) and the median survival time was 24.7 months. The MTD of amrubicin and cisplatin were determined as 30 mg/m2 and 60 mg/m2. A dose of 25 mg/m2 amrubicin and cisplatin 60 mg/m2 was recommended in this regimen. Conclusions: This regimen with concurrent TRT in LD-SCLC is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting. Clinical trial information: UMIN000005816.

Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.

2574 Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.

Abstract OT1-01-06: PIQHASSO: Open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients (pts) with locally advanced (LA) or metastatic HER2 (-) and triple-negative breast cancer (TNBC) (study PQR309-007)

Abstract BACKGROUND: The PI3K/AKT/mTOR (PAT) pathway alteration has been strongly implicated in breast cancer and may contribute to resistance to available therapy. PQR309 is an oral pan-PI3K and mTOR inhibitor that penetrates the blood-brain barrier. Experiments of eribulin in combination with PI3K inhibitors in luminal and TNBC pre-clinical models enhanced antitumor activity. TRIAL OBJECTIVES: The primary objectives of the study are: to identify the maximum tolerated dose (MTD), evaluate the efficacy, safety and tolerability as well as the pharmacokinetics (PK) of PQR309 in combination with eribulin. In addition, exploratory objectives include assessments of: PAT pathway alterations prior to treatment, pharmacodynamics (PD) activity of PQR309 in combination with eribulin and correlation of PAT pathway alterations and PD activity with PQR309 and eribulin PK. TRIAL DESIGN: This is an open label, non-randomized, multicenter phase 1/2b clinical trial (dose escalation followed by expansion part) of PQR309 p.o. in combination with the standard dose of eribulin mesylate (1.4 mg/m2) in patients with LAMBC until progression or unacceptable adverse events (AE). The dose escalation part of the study will first investigate PQR309 administered in a continuous daily (q.d.) and two intermittent treatment schedules in combination with standard administration of eribulin mesylate in patients with HER2 negative LAMBC following the “modified” 3 by 3 design. MTD is defined as the highest dose level at which ≤1 of 6 pts experiences dose-limiting toxicity (DLT) during the 1st cycle. After the MTD of PQR309 in combination with eribulin has been defined in all the three treatment schedules, one schedule will be selected, based on the overall evaluation of clinical data from the dose escalation part of the study, for further evaluation of efficacy in the expansion part of the study. The expansion part of the trial applies Simon's MiniMax two-stage design. At the first stage, > 3 pts with TNBC with clinical benefit (CB) among 14 pts will be necessary to continue to the second stage. At the study end, > 9 pts with CB out of 28 pts are required to reject the null hypothesis. With this design, there is an 80% probability of a positive finding if the true clinical benefit rate (CBR) is ≥ 43% and a 5% probability of a positive finding if the true CBR is ≤ 21%. ELIGIBILITY: Women with HER2- LAMBC with two to 5 prior chemotherapy regimens in advanced disease. Adequate organ function and performance status. Phase II specific selection criteria are: triple negative LAMBC and RECIST v1.1 evaluable disease. ACCRUAL: Approximately 60 patients will be enrolled in approximately 10 sites Recruitment opened in March 2016. TRIAL REGISTRATION: NCT02723877. Date of registration: 21/12/2015. First patient included: 04/04/2016. Citation Format: López-Miranda E, Gávila J, Pernas S, Saura C, Oliveira M, Serra V, Schmid P, Lord S, Paez D, Perez J, Llombart A, Petrovic K, Dimitrijevic S, Cortes J. PIQHASSO: Open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients (pts) with locally advanced (LA) or metastatic HER2 (-) and triple-negative breast cancer (TNBC) (study PQR309-007) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-06.

External beam radiotherapy for unresectable hepatocellular carcinoma, an international multicenter phase I trial, SAKK 77/07 and SASL 26

PurposeTo assess feasibility and safety of conventionally fractionated radiotherapy (cfRT) in patients with hepatocellular carcinoma (HCC).MethodsPatients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh Score (CPS) A or B disease were included in a phase I multicenter trial. Metastatic HCC were allowed if ≥90% of total tumor volume was located within the liver. Patients were enrolled onto five dose-escalation levels (54–70Gy in 2Gy fractions) based on a modified 3 + 3 design, with cohorts of five patients instead of three patients in dose levels 4 and 5. Primary trial endpoint was dose-limiting toxicity (DLT), as specifically defined for 17 clinical and nine laboratory parameters as grade ≥3 or ≥4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of ≤16.7% in dose levels 1–3, and ≤10% in dose levels 4–5. Best objective response of target liver lesions and adverse events (AE’s) were assessed as secondary endpoints.ResultsThe trial was terminated early in DL 3 due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary and 18 for the secondary endpoints. Maximum tolerated dose was not reached. One patient in dose level 1, and one patient in dose level 2 experienced DLT (lipase > 5xULN, and neutrophils <500/μL respectively). However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients.Overall, 56% of patients had a partial response and 28% showed stable disease according to RECIST. No signs of radiation induced liver disease (RILD). Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact.ConclusionConventionally fractionated radiotherapy of 58Gy to even large HCC was safe for patients with CPS A and B. 62Gy was delivered to three patients without any sign of clinically relevant increased toxicity. The maximum tolerated dose could not be determined.Trial registrationClinicalTrials.gov identifier NCT00777894, registered October 21st, 2008.

Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study

PurposeCabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI.MethodsPatients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m2, respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed.ResultsIn C-2, three patients receiving cabazitaxel 25 mg/m2 experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m2. In C-3, two patients receiving 20 mg/m2 experienced DLTs; MTD was 15 mg/m2. C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3–4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m2) than expected (26.4 L/h/m2), but similar in C-2 (23.5 L/h/m2) and C-3 (27.9 L/h/m2). CL/BSA in C-4 was 18.1 L/h/m2. Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74–1.91), but decreased 23% in C-4 (0.77; 0.39–1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3–4 toxicities and pharmacokinetic parameters.Conclusions Mild–moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild–moderate HI, and a contraindication in patients with severe HI, are justified based on safety data.

P3.02c-001 Phase I Study of Salazosulfapyridine Targeting Cancer Stem Cells in Combination with CDDP and Pemetrexed for Chemo-Naïve Advanced Non-Sq NSCLC: Topic: Targeted Therapy

Variant splicing isoforms of CD44 (CD44v) are a marker of cancer stem cells (CSCs) in solid tumors. CD44v stabilizes the glutamate-cystine transporter subunit xCT and thereby promotes synthesis of the intracellular antioxidant glutathione and protects CSCs from oxidative stress. Salazosulfapyridine (SASP) is an inhibitor of xCT activity, and, in combination with cisplatin (CDDP), it attenuates the increase in the proportion of CD44v-positive tumor cells during the growth of tumor xenografts in mice. Individuals with advanced (stage IIIB or IV) nonsquamous non–small cell lung cancer are eligible to enroll in a phase I dose-escalation study (standard 3+3 design) of SASP in combination with CDDP and pemetrexed (PEM) as first-line treatment. Patients receive SASP daily as well as CDDP (75 mg/m2) and PEM (500 mg/m2) on day 1 of a 21-day cycle. The primary end point is the percentage of patients who experience dose-limiting toxicity (DLT) between administration of the first dose of SASP (day 1) and day 21. From April 2015 to January 2016, 15 patients were enrolled in the study (mean age, 64 years; age range, 42–74 years; male/female ratio, 10/5; ECOG performance status 0/1 ratio, 6/9). Immunohistochemical staining of tumor biopsy specimens revealed that the proportion of CD44v-positive cells was >10% in 9 patients before SASP treatment. No DLT was observed in the first three patients treated at SASP dose level 1 (500 mg TID) or those treated at dose level 2 (1000 mg TID). At dose level 3 (1500 mg TID), two of three patients experienced a DLT (anorexia of grade 3). We enrolled additional patients at dose level 2 and two of the total of five patients treated at this dose level experienced DLTs (hypotension or pneumonitis, each of grade 3). To confirm the safety of dose level 1, we enrolled additional patients at this dose level and one of the total of six patients treated at this dose level experienced DLTs (AST and ALT elevation, each of grade 3). Exposure of SASP following oral administration varied markedly among individuals according to ABCG2 and NAT2 genotypes as previously reported. SASP 500 mg TID was the recommended dose when administered with CDDP plus PEM.

Thioguanine Combined with Decitabine Can Overcome Resistance to Hypomethylating Agents: Final Results of a Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/Decitabine Combination in Patients with Advanced Myeloid Malignancies

Background: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that combination treatment with thioguanine and decitabine can restore therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. To test the safety and synergistic efficacy of this combination in patients with advanced myeloid malignancies, we performed a Phase I dose-escalation trial of thioguanine given with decitabine.Patients and Methods: Patients with untreated AML ≥60 years of age and ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. The primary objective was to determine the maximum tolerated dose (MTD) of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Patient-specific pharmacodynamic measures to assess the biologic activity of thioguanine-decitabine were also performed. These included an in vitro chemosensitivity assay, BH3 profiling to measure the degree to which the leukemic blasts were primed for apoptosis, and genome-wide analysis of DNA methylation changes.Results: Twelve patients (median age 67; range 56-83) with de novo AML (n=1), secondary AML (n=6), relapsed/refractory AML (n=4), and chronic myelomonocytic leukemia (CMML) (n=1) were treated. Three patients experienced dose-limiting toxicity (DLT), which were acute renal failure requiring hemodialysis (80 mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120 mg/m2), and grade 4 sepsis preventing continued treatment (120 mg/m2). Thioguanine at 80 mg/m2 was determined to be the MTD. Eleven of the 12 patients completed the first induction cycle, and 6 patients completed a second, identical induction cycle. The median number of cycles administered was 3 (range 1-8). One patient experienced a DLT prior to the first response assessment and was removed from study. The ORR in this intent-to-treat study was 67% (8/12). Six patients achieved a CR or CRi, one obtained a morphologic leukemia-free state, and one patient had a PR. Responses were observed in all disease types. Five of the 8 responses, including 4 CR/CRi, were achieved with thioguanine at 80 mg/m2, suggesting no loss of efficacy at the MTD compared with the higher dose level. All 11 evaluable patients had ≥50% reduction in bone marrow blast percentages after induction therapy. Six patients had previously received single-agent hypomethylating therapy, and 5 (83%) of these patients responded, demonstrating that thioguanine-decitabine can rescue prior hypomethylating agent failure. Out of the 8 responders, four (50%) proceeded to allogeneic stem cell transplantation (SCT), two relapsed after CR or CRi, one had a CNS-only relapse after achieving a CR, and one patient experienced DLT and was removed from the study. Of the four patients who proceeded to allogeneic SCT, two patients died in CR from transplant-related toxicity, one relapsed, and one patient remains alive and in remission greater than 2 years. Median PFS in responding patients was 42 weeks (range, 10-not reached, weeks). In vitro pharmacodynamic studies currently have been completed on samples from the first 6 patients treated on this trial. The chemosensitivity assay results on pre-treatment mononuclear cells directly correlated with initial response. In addition, significant apoptotic priming of the blasts, as suggested from BH3 profiling, also corresponded to initial clinical response.Conclusions: Thioguanine-decitabine can be administered safely and induce remission, even among patients who had previously been treated with hypomethylating agents. Intriguingly, preliminary results from the chemosensitivity screening assay and BH3 profiling correlated well with clinical responses. Additional correlative studies including DNA methylation analysis are ongoing to better understand the mechanism of synergy between thioguanine and decitabine. A multi-center Phase II trial is planned. DisclosuresJurcic:Astellas: Research Funding. Letai:Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

Phase I Trial of Targeted Alpha-Particle Therapy with Actinium-225 (225Ac)-Lintuzumab and Low-Dose Cytarabine (LDAC) in Patients Age 60 or Older with Untreated Acute Myeloid Leukemia (AML)

Background:225Ac-lintuzumab is a radioimmunoconjugate composed of 225Ac (t½=10 days), which emits 4 α-particles, linked to a humanized anti-CD33 monoclonal antibody. Short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes such as 225Ac may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. An initial phase I trial in 20 patients with relapsed/refractory AML showed that a single infusion of 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity (Jurcic et al. ASH, 2011). We conducted a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC.Patients and Methods: Patients ≥ 60 years with untreated AML not candidates for standard induction therapy (e.g., antecedent hematologic disorder, poor-risk cytogenetic or molecular features, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice a day for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, 2 fractions of 225Ac-lintuzumab were given 1 week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab then spironolactone for 1 year afterward. Four dose levels of 225Ac-lintuzumab were studied using a 3+3 design. Dose escalation proceeded if < 33% of patients in a cohort experienced dose-limiting toxicity (DLT).Results: Eighteen patients (median age, 77 years; range, 68-87 years) completed therapy. Twelve (67%) had prior myelodysplastic syndrome (MDS), for which 10 (83%) received therapy with hypomethylating agents (n=9) or allogeneic hematopoietic cell transplantation (n=1). One patient (6%) had chronic myeloid leukemia in molecular remission prior to developing AML. Eleven patients (61%) had intermediate-risk and 7 (39%) had poor-risk disease by NCCN criteria. Median CD33 expression was 81% (range, 30-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=6) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. Two patients experienced DLT (grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy), one each in the 1 and 2 µCi/kg/fraction cohorts. Although the MTD was not reached, 2 µCi/kg/fraction was chosen as the phase II dose to limit prolonged myelosuppression. Hematologic toxicities included grade 4 neutropenia (n=5) and thrombocytopenia (n=9). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=5), other infections (n=3), atrial fibrillation/syncope (n=1), transient creatinine increase (n=1), generalized fatigue (n=1), hypokalemia (n=1), mucositis (n=1), and rectal hemorrhage (n=1). Thirty- and 60-day mortality rates were 0% and 17%, respectively. Eleven of 14 patients (79%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 66%; range, 19-100%). Objective responses (2 CR, 1 CRp, 2 CRi) were seen in 5 of the 18 patients (28%), but only at doses ≥ 1 µCi/kg/fraction (Table 1). One of the responders received 15 cycles of azacitidine for prior MDS. All responses occurred after 1 cycle of therapy, in contrast to historical data with LDAC alone, where the median time to response was 3 cycles. Median progression-free survival (PFS) for all patients was 2.7 months (range, 1.0-31.8+ months). Median overall survival (OS) was 5.6 months (range, 1.6-32+ months). Median response duration was 5.6 months (range, 4.9-32+ months). Peripheral blood blast counts were a strong predictor of response. Among 38 patients treated in the current and initial phase I trials, responses were seen in 8 of 19 patients (42%) with blast counts < 200/µL, compared with 0 of 17 patients with blast counts ≥ 200/µL (P=0.002). This difference is likely due to decreased marrow targeting in patients with higher circulating blast counts when the subsaturating antibody doses used in this trial are given.Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and induce remission in older patients with untreated AML. A phase II trial of 225Ac-lintuzumab monotherapy at 2 µCi/kg/fraction using hydroxyurea, if needed, to lower peripheral blast counts prior toadministration will be undertaken to determine response rate, PFS, and OS in this patient population. [Display omitted] DisclosuresJurcic:Forma Therapeutics: Research Funding; Seattle Genetics: Research Funding; Kura Oncology: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees; Bayer: Consultancy; Alexion Pharmaceuticals: Consultancy; Merck & Co.: Consultancy; Astellas: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding; Daiichi-Sankyo: Research Funding. Levy:Janssen: Speakers Bureau; Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Park:Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Ravandi:Actinium Pharmaceuticals, Inc.: Research Funding. Perl:Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Ac-225-Lintuzumab.

1002P - Phase I study of ribociclib plus cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

The majority of Human Papilloma Virus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) has inactivation of p16, an inhibitor of the Cyclin-Dependent Kinases (CDK) 4 and 6, and 20-30% present CCND1 amplification. These alterations promote cell cycle progression and tumor proliferation. EGFR upregulation could also induce elevation of cyclin D1 and CDK4. Cetuximab, an anti-EGFR mAb, improves survival in combination with platinum-based chemotherapy in recurrent SCCHN. This study is investigating the combination of ribociclib, an orally highly selective inhibitor of CDKs 4/6, and cetuximab in recurrent SCCHN. p16-negative recurrent and/or metastatic SCCHN patients (pts) who progress after platinum-based chemotherapy were included in this phase 1 study. All the pts received cetuximab at the recommended dose (400 mg/m2 followed by 250 mg/m2/week, IV), combined with ribociclib (3 weeks on/1 week off), in a classical 3 + 3 dose-escalation design. The first dose level of ribociclib was 400 mg/day and the second dose level 600 mg/day. The primary endpoint was to determine the maximum tolerated dose (MTD) of Ribociclib in combination with cetuximab. Between April 2015 and January 2016, 10 pts (median age: 62.5 years; site location: larynx (2), hypopharynx (2), oropharynx (2), oral cavity (4)) were enrolled, including 6 pts previously treated with cetuximab. No dose limiting toxicities (DLTs) were observed at the first dose level. At the second dose level, 1 pt presented rapid disease progression and was therefore replaced as he could not be evaluated for toxicity. One pt out of 6 experienced DLT (Grade 4 thrombopenia lasting more than 7 days). The most common grade 3/4 treatment-related adverse events were neutropenia (n = 2), anemia (n = 2), thrombopenia (n = 1), hypocalcemia (n = 2), hypokaliemia (n = 2), hypomagnesemia (n = 1) and hypoglycemia (n = 1). No objective responses were observed but 4 pts achieved a stable disease according to RECIST v1.1, including 2 pts previously treated with cetuximab. The MTD of ribociclib in combination with standard dose of cetuximab is 600mg daily (3 weeks on/1 week off). An expansion cohort is currently ongoing.

Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial

AbstractThe objectives of a phase 1/2 trial of pomalidomide with dexamethasone for the treatment of light chain (AL) amyloidosis were to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose, and hematologic and clinical response. A 3+3 dose-escalation phase (15 patients) was followed by an expansion cohort (12 patients) enrolled at the MTD. Pomalidomide was administered at 2 and 3 mg on days 1 to 28 (cohorts 1 and 2) and 4 mg on days 1 to 21 (cohort 3) every 28 days, with weekly dexamethasone at a dose of 20 mg. Twenty-seven patients with previously treated AL were enrolled, 15 during dose escalation (6 at 2 mg, 3 at 3 mg, and 6 at 4 mg) and 12 during dose expansion (all at 4 mg). One patient experienced dose-limiting toxicity at 4 mg; the MTD was determined as 4 mg. The most common grade ≥3 drug-related adverse events included myelosuppression and fatigue. Overall, hematologic response (HR) was 50% in 24 evaluable patients. The median time to best HR was 3 cycles, and median duration of HR was 15 months. Median overall survival has not yet been reached, with a median follow-up of 17.1 months and median event-free survival of 17.8 months. This trial was registered at www.clinicaltrials.gov as #NCT01570387.

An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors.

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.

A phase Ib dose escalation, safety, and tolerability study of sonidegib in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

371 Background: Sonidegib (LDE225) is a potent, selective, and orally bioavailable inhibitor of smoothened receptor that demonstrated preclinical activity in combination with gemcitabine (GEM). Here, we present data from a phase 1b trial of sonidegib in combination with GEM in patients (pts) with pancreatic adenocarcinoma (PA). Methods: Pts with histologically or cytologically confirmed, locally advanced, or metastatic PA who had not been treated previously or had progressed despite prior chemotherapy (other than GEM) were included in the study. Dose escalation started with sonidegib 400 mg, once a day, in combination with GEM 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle. Results: A total of 18 pts were enrolled (9 pts each the in dose escalation and dose expansion phases). Pts discontinued the study because of disease progression (n = 11, 61.1%), consent withdrawal (n = 3, 16.7%), administrative problems (n = 3, 16.7%), and grade 3 or 4 blood creatine kinase (CK) elevation (n = 1, 5.6%). Three of 9 pts in dose escalation phase experienced dose-limiting toxicities during the first 8 weeks including grade 3 mucositis (n = 1), grade 3 CK elevation (n = 1), and grade 3 aspartate aminotransferase elevation (n = 1). Drug-related adverse events (AEs) of all grades were reported in 14 pts (77.8%) and grade 3 or 4 AEs were reported in 10 pts (55.6%). The most commonly reported AEs were anemia and nausea. No pharmacokinetic (PK) interaction was observed. Based on considerations of the statistical model, clinical assessment of safety, tolerability, PK, and pharmacodynamic results, maximum-tolerated dose and recommended dose were established as 400 mg of sonidegib in combination with the fixed standard dose of GEM (1000 mg/m2).The objective response rate was 11.1% and the median progression-free survival (PFS) was 4.9 months. Conclusions: The combination of sonidegib and GEM was generally well tolerated with moderate activity. Although no formal comparison can be made due to small sample size of this study, this combination provided a median PFS comparable to the current standard of care without conferring any additional clinical benefit. Clinical trial information: NCT01487785.

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.

Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton9s tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm 3 , platelets > 50,000/mm 3 , and creatinine 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC 3 or platelets 3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin9s lymphoma is off-label. Kuruvilla: Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith: Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu: Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks: Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd: Pharmacyclics: Research Funding. Blum: Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

Phase I Trial of Targeted Alpha-Particle Immunotherapy with Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) and Low-Dose Cytarabine (LDAC) in Older Patients with Untreated Acute Myeloid Leukemia (AML)

Background: The use of short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes for radioimmunotherapy may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. 225Ac-lintuzumab consists of a radiometal that emits four α-particles linked to an anti-CD33 antibody. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-tumor activity against relapsed/refractory AML across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC.Patients and Methods: Patients ≥ 60 years with untreated AML not suitable for standard induction chemotherapy (e.g., antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice daily for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, two fractions of 225Ac-lintuzumab were given one week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward. 225Ac doses were escalated using a 3+3 design. Four dose levels were studied with a total accrual of up to 24 patients. In planned analyses, dose escalation proceeded if < 33% of patients in a cohort experienced dose-limiting toxicity (DLT).Results: Fourteen patients (median age, 77 years; range, 68-87 years) completed therapy. An additional patient received only one of two planned fractions of 225Ac-lintuzumab due to technical issues and is excluded from analysis. Nine (64%) had prior myelodysplastic syndrome, for which seven received prior therapy with hypomethylating agents (n=6) or allogeneic hematopoietic cell transplantation (n=1). One patient (7%) had chronic myeloid leukemia in molecular remission prior to development of AML. Nine patients (64%) had intermediate-risk and five (36%) had unfavorable cytogenetics. Median CD33 expression was 81% (range, 45-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=2) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. DLT was seen in one patient at 1 µCi/kg/fraction who had grade 4 thrombocytopenia with marrow aplasia for more than 6 weeks following therapy. Hematologic toxicities included grade 4 neutropenia (n=4) and thrombocytopenia (n=6). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=7), pneumonia (n=4), bacteremia (n=1), cellulitis (n=1), transient creatinine increase (n=1), hypokalemia (n=1), rectal hemorrhage (n=1), and generalized weakness (n=2). Eight of 11 patients (73%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 72%; range, 34-100%). Seven (64%) had blast reductions of at least 50%. Objective responses (1 CR, 1 CRp, 2 CRi) were seen in four of the 14 patients (29%) after one cycle of therapy (Table 1). Responses were seen only at doses ≥ 1 µCi/kg/fraction (4 of 11 patients, 36%). Median progression-free survival (PFS) was 2.7 months (range, 1.7-16.9 months). Median overall survival (OS) was 5.5 months (range, 2.2-24 months).Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and produce remission in older patients with untreated AML. Dose escalation continues to define the MTD. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS.Table 1Objective ResponsesResponseDose Level (μCi/kg/fraction)Total (n=14)0.5 (n=3)1 (n=6)1.5 (n=3)2 (n=2)CR001 (33%)01 (7%)CRp0001 (50%)1 (7%)CRi01 (17%)1 (33%)02 (14%)Overall Response01 (17%)2 (67%)1 (50%)4 (29%)Abbreviations: CR, complete remission; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete count recovery. DisclosuresJurcic:Ambit Biosciences: Research Funding; Astellas Pharma US, Invc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Sunesis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Bayer Pharmaceuticals: Consultancy; Merck and Co.: Consultancy; Celgene Corp.: Research Funding; Actrinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ac-225-lintuzumab is an investigational agent being developed for the treatment of acute myeloid leukemia.. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Park:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy. Levy:Takeda: Consultancy. Perl:Actinium Pharmaceuticals, Inc.: Research Funding. Earle:Actinium Pharmaceuticals, Inc.: Employment. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

An Open-Label, Phase I Study of Dasatinib in Combination with Decitabine in Patients (Pts) with Accelerated or Blastic Phase Chronic Myeloid Leukemia (CML)

▪Background: Current treatment for advanced phase CML remains unsatisfactory. Dasatinib induces major cytogenetic response (MCyR) in 31% and 37% of pts with imatinib-resistant or -intolerant accelerated (AP) and blast phase (BP), respectively (Cortes 2007). Hypermethylation is associated with disease progression in CML. In pts with imatinib-refractory CML-AP and CML-BP, low dose decitabine induced MCyR in 12% and 17% of pts, respectively, with similar rates achieved combining decitabine with imatinib (Issa 2005, Oki 2007). The reported synergy between imatinib and decitabine depends upon residual sensitivity to imatinib (La Rosee 2004). We investigated whether improved responses might be achieved through synergy between dasatinib, a 2nd generation tyrosine kinase inhibitor (TKI) and decitabine.Methods: Pts age 18 years or older with CML-AP, CML-BP, or Philadelphia chromosome (+) acute myeloid leukemia (Ph+AML) were enrolled in this phase 1 study regardless of previous TKI therapy. Pts were assigned to 2 schedules using a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). The starting schedule was decitabine 10mg/m2 daily for 10 days and dasatinib 100 mg orally daily (schedule A), and decitabine 20mg/m2 daily for 10 days with dasatinib 100 mg (schedule B). The next dose level (target dose) was decitabine 10mg/m2 daily for 10 days (schedule A) or 20 mg/m2 daily for 10 days (schedule B) with dasatinib 140 mg orally daily. The primary objective was to determine the MTD of the combination. The secondary objectives are to determine the rate of overall hematologic response (OHR) (2 cycles required to be evaluable for response), response duration (RD), overall survival (OS), and toxicity profile. OHR includes complete hematologic response (CHR), no evidence of leukemia (NEL), and minor hematologic response (MiHR). CHR is defined as normal WBC, no blasts or promyelocytes in peripheral blood (PB), ANC ≥1x109/L, platelets >100 x109/L, PB basophils < 5%, ≤ 5% blasts in bone marrow (BM), and no extra-medullary disease. NEL is the same criteria as CHR except for platelets between ≥ 20 x109/L and <100x109/L or ANC between ≥ 0.5x109/L and < 1x109/L. MiHR is defined as <15% blasts in PB and BM, <30% blasts + promyelocytes in BM and PB, <20% basophils in PB, and no extra-medullary disease.Results: A total of 15 pts were enrolled (2 AP, 11 BP, 2 Ph+AML); 13 were evaluable for response. The remaining 2 pts were not evaluable for response since they did not complete 2 cycles of therapy as defined in the protocol, due to drug toxicity (n=1) and insurance issues (n=1). Eleven pts had received prior TKI therapy with a median of 1 TKI per pt (range, 1-4). Two pts had a kinase domain mutation (V299L, E255K); one other patient had a 162 bp deletion. No DLT was observed at the starting dose level for either schedule. The MTD was thus established at decitabine 10mg/m2 and dasatinib 140 mg at which 1 of 6 pts treated experienced dose-limiting toxicity (DLT) in the form of grade 3 heart failure considered possibly related to dasatinib. Pts received a median of 2 treatment cycles (range 1-10) and 2 pts are still receiving study therapy. Nine (69%) pts achieved OHR (4 CHR, 2NEL, 3 MiHR). A MCyR was achieved by 38% (5/13). In addition, 1 pt achieved MCyR after stem cell transplantation (SCT) (CHR with DAC + dasatinib prior to SCT). Median duration of OHR was not reached (RD for each of the 9 pts was 4, 1, 31+, 2, 3, 1, 18+, 2+, 3+ months, respectively). Median OS was 12 months (95% CI: 2.3- not reached). A total of nine (60%) pts died, all due to disease progression. Two pts have ongoing complete cytogenetic response with combination therapy (for 7+ and 10+ cycles, respectively). The remaining 4 surviving pts all received SCT. Two of them had achieved MCyR, 1 CHR, and 1 MiHR with DAC + dasatinib prior to SCT. Grade 3-4 nonhematological toxicity was reported in 13 (87%) pts, most frequent toxicities being infections (27%), bleeding (20%), and acute renal failure (20%).Conclusion: Combination therapy with decitabine and dasatinib is well tolerated and active in advanced phase CML. A phase 2 portion of the study has opened now to determine the efficacy of this combination and whether there is a difference in outcome by treatment schedule. DisclosuresOff Label Use: Hypermethylation is associated with disease progression in CML. Previous studies have reported that the synergy between imatinib and decitabine depends upon residual sensitivity to imatinib. Given the potency of dasatinib, we are investigating whether improved responses might be achieved through synergy between dasatinib and decitabine. Daver:ImmunoGen: Other: clinical trial, Research Funding. Cortes:BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.

A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors

BackgroundVolasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors. Patients and methodsThis open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2h, starting at 100mg in the first dose cohort. Nintedanib was administered orally at a dose of 200mg twice daily. The first treatment cycle comprised 28 days (days 1–7 and days 9–28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2–21. The primary objective was the MTD of volasertib in combination with nintedanib. ResultsThirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure. ConclusionsVolasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity.