Dose-limiting Toxicities In Cycle Research Articles

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma.

Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Oral cabozantinib (25mg/m2 ) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m2 ) and cyclophosphamide (250mg/m2 ) were administered intravenously (IV) on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m2 IV days 1-5, cyclophosphamide 250mg/m2 IV days 1-5, and cabozantinib 25mg/m2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control.

Dose escalation of a phase 1b/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with metastatic solid tumors.

2503 Background: Modakafusp alfa (TAK-573) is a first-in-class immune-targeting attenuated cytokine designed to deliver attenuated interferon alpha-2b (IFNα2b) moieties to CD38-expressing cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody. Specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Modakafusp alfa has demonstrated immune cell activation and antitumor activities in preclinical mouse models, including tumor models that do not express CD38, and has shown strong clinical responses and immune activation in pts with refractory/relapsed multiple myeloma. The dose-escalation phase of this phase 1b/2 study (NCT04157517) investigated safety, pharmacokinetics, immunogenicity, pharmacodynamics (PD), and preliminary efficacy of modakafusp alfa in metastatic solid tumors. Methods: Adult pts with advanced/metastatic solid tumors received modakafusp alfa IV on day 1 of a 21-day cycle (Q3W). Dose escalation started at 0.1 mg/kg and proceeded based on cycle 1 safety data via a Bayesian model with overdose control principles. Results: Twenty-one pts were dosed in the escalation phase at 0.1 (n = 3), 0.2 (n = 3), 0.4 (n = 3), 0.75 (n = 3), 1.0 (n = 3), and 1.5 mg/kg (n = 6) Q3W; median age 63 y (range 42–80); male 57.1%; GI malignancies 71.4%; median prior lines of therapy 3 (range 2–7). Two pts had dose-limiting toxicities in cycle 1 at 1.5 mg/kg; 1 pt with baseline bone infiltration had grade 4 thrombocytopenia and 1 pt had grade 3 confusion. As of Nov 2021, across all doses, pts received a median of 2 treatment cycles (range 1–11). Modakafusp alfa treatment-related adverse events (TRAEs) reported in 81% of pts included infusion-related reactions (52.4%), chills (47.6%), and nausea (33.3%). Grade ≥3 TRAEs reported in 42.9% of pts included neutropenia (14.3%) and hypertension (9.5%). There was a greater than dose proportional exposure increase in the dose range 0.1–1.5 mg/kg, with no exposure accumulation after Q3W dosing. Incidence rate of post-treatment anti-drug antibody (ADA) was 100%. PD data suggested saturation of peak IFN pathway modulation at ≥0.2 mg/kg in the peripheral blood with duration of modulation increasing with dose. Among the 14 response-evaluable pts, 7 had best response of stable disease, including 1 with cutaneous melanoma who had 21% target lesion reduction. Conclusions: Modakafusp alfa had a manageable safety profile in the dose range 0.1–1.5 mg/kg in pts with solid tumors. Proof of mechanism was validated. The recommended phase 2 dose was determined as 1.0 mg/kg Q3W based on assessment of holistic data and will be tested in combination with a checkpoint inhibitor in selected tumor types. Characterization of ADA and its impact is ongoing. Clinical trial information: NCT04157517.

Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma.

Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated. Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.

Evorpacept (ALX148), a CD47-Blocking Myeloid Checkpoint Inhibitor, in Combination with Azacitidine: A Phase 1 / 2 Study in Patients with Myelodysplastic Syndrome (ASPEN-02)

Evorpacept (ALX148), a CD47-Blocking Myeloid Checkpoint Inhibitor, in Combination with Azacitidine: A Phase 1 / 2 Study in Patients with Myelodysplastic Syndrome (ASPEN-02)

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study

Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1-4, oral prednisone 60 mg/m2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m2 on days 1-4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). Genentech.

A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma.

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

Vincristine Sulfate Liposome Injection (VSLI) with Bendamustine and Rituximab As First-Line Therapy for Indolent B-Cell Lymphomas: A Phase 1 Study

Vincristine Sulfate Liposome Injection (VSLI) with Bendamustine and Rituximab As First-Line Therapy for Indolent B-Cell Lymphomas: A Phase 1 Study

471P - Lurbinectedin (LUR) in combination with irinotecan (IRI) in patients (pts) with advanced solid tumours

BackgroundLUR is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this trial. MethodsPhase I trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors, enrolled following a standard 3+3 dose escalation design. Results39 pts were treated at 5 dose levels (DL); 13 at the recommended dose (RD). 56% were females, 69% had ECOG PS=1; median age was 58 years; median of 2 prior chemotherapy lines for advanced disease (range, 0−4) per pt. RD was defined as LUR 2.0mg/m2 on D1 + IRI 75mg/m2 on D1 and D8 q3w + GCSF. Dose-limiting toxicities in Cycle 1 were observed in 2/3 evaluable pts at the maximum tolerated dose (MTD) and in 3/13 evaluable pts at the RD. At the MTD and the RD, DLTs were skipping IRI D8 doses due to grade (G) 3-4 neutropenia (n=3 patients) or G2-4 thrombocytopenia (n=2). At the RD common G1/2 toxicities were nausea, vomiting, fatigue, diarrhea, anorexia and neuropathy; G3/4 hematological abnormalities comprised neutropenia (33%), but no thrombocytopenia. Objective RECIST responses were documented in 6/34 evaluable pts (18%): 3/11 pts with small cell lung cancer (SCLC), 2/2 pts with endometrial carcinoma (EC) and 1/3 pts with glioblastoma (GB). Most responses (5/12 evaluable patients [42%]) were at the RD. One pt with EC has an ongoing PR after 20 cycles. Prolonged SD>4 months were observed in pancreatic carcinoma (3/6 pts), soft tissue sarcoma (STS) (5/9 pts) and SCLC (6/11, including 4 with SD for 6, 9, 11 and 26+ months). ConclusionsThe combination of LUR and IRI is well tolerated, with no unexpected toxicities. Myelosuppression was dose-limiting, but predictable and manageable. The RD is LUR 2.0mg/m2 on D1 + IRI 75mg/m2 on D1 and D8 q3w with GCSF. Notable antitumor activity was observed, especially in SCLC, EC, GB and STS. Expansion in these indications is warranted. Clinical trial identificationNCT02611024. Legal entity responsible for the studyPharmaMar SA. FundingPharmaMar. DisclosureS. Ponce Aix: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Roche, BMS, MSD. G. Coté: Advisory / Consultancy: Agios; Research grant / Funding (institution), Research funding to my institution for the conduct of clinical trials; no salary support: Epizyme, Eisai, Macrogenics, Boston Biomedical, Plexxicon, Merck KGaA/EMD Serono Research and Development Institute, CBA Inc, Bayer. R. Nuñez: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. M. Siguero: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. M. Insa: Full / Part-time employment: PharmaMar. M. Cullell-Young: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. C. Kahatt: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. A. Zeaiter: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. L. Paz-Ares: Advisory / Consultancy: Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Clovis Oncology; MSD; Novartis; Pfizer; Roche; Takeda. All other authors have declared no conflicts of interest.

A phase I/II trial of VX15/2503 in children, adolescents, and young adults with relapsed or refractory solid tumors (ADVL1614).

e21519 Background: Semaphorins regulate tumor progression, immune responses, and angiogenesis. SEMA4D was identified as a candidate proto-oncogene by a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice. SEMA4D is expressed on tumors, including osteosarcoma, and in the tumor microenvironment. VX15/2503, a humanized IgG4 monoclonal antibody, binds SEMA4D, blocks receptor interaction and enhances the anti-tumor immune response in preclinical studies. This trial aimed to determine the tolerability and recommended dose of VX15/2503 in patients with relapsed/refractory solid tumors and activity in patients with osteosarcoma. Methods: Part A enrolled patients age≤ 21y with refractory solid tumors to assess the tolerability of VX15/2503 (20 mg/kg) IV every 14 days x 2 doses/cycle. The recommended dose was one that was tolerated and achieved sustained target saturation. Up to 6 additional children were enrolled to assess pharmacokinetics (PK). In part B, a two-stage design was used to assess the activity of VX15/2503 in patients with measurable, relapsed /refractory osteosarcoma. In part B1 patients > 21-30y accrued concurrently with part A; Part B2 (patients £ 21y) was initiated after the pediatric recommended dose was determined. Correlative studies including target saturation by VX15/2503 were required. Results: 18 eligible patients enrolled, 16 evaluable for toxicity. In part A (n = 12) the median (range) age was 12.5 (1-20) y. Diagnoses included osteosarcoma (8), neuroblastoma (2), other (2). No dose limiting toxicities (DLTs) were observed. In Part B1, (n = 6) median (range) age was 22.5 (22-30) y; one patient had cycle 1 DLTs (grade 3 acute kidney injury, creatinine increase, arthralgia and myalgia); a second patient had a later cycle DLT (grade 4 pericardial effusion). Given only 1/18 had a cycle 1 DLT, this did not impact dose selection. T-cell saturation by VX15/2503 was adequate and sustained in all patients. Conclusions: VX15/2503 was well tolerated at 20 mg/kg IV every 2 weeks and is the recommended dose in children, adolescents and young adults. The activity in osteosarcoma is under evaluation. Future trials combining VX15/2503 with novel agents are in development. Clinical trial information: NCT03320330.

Trilaciclib (G1T28): A cyclin dependent kinase 4/6 inhibitor, in combination with etoposide and carboplatin (EP) for extensive stage small cell lung cancer (ES-SCLC)—Phase 1b results.

8568 Background: Chemotherapy (chemo) has significant clinical utility, however consequent damage to hematopoietic stem and progenitor cells (HSPCs) and the immune system may limit activity. If chemo-mediated anti-tumor activity was maximized, while minimizing myelosuppression and immunosuppression, patient outcomes would be improved. Trilaciclib (T) is an intravenous CDK4/6 inhibitor in development to reduce myelosuppression and preserve immune system function during chemo. HSPCs are dependent on CDK4/6 for proliferation. Preclinical data demonstrated that transient T-induced G1 cell cycle arrest renders HSPCs resistant to chemo cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of anti-tumor immunity and activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess dose limiting toxicities (DLTs), safety, tolerability, hematological profile, PK, and anti-tumor activity of T administered prior to EP. Phase 1b was open-label, dose-finding, and the ongoing Phase 2a is randomized (1:1), double-blind. Eligible pts had confirmed diagnosis of ES-SCLC, adequate organ function, ECOG PS 0-2, no prior chemo, and no symptomatic brain metastases. Results: 19 pts were enrolled in the Phase 1b: 10 pts received T 200 mg/m2 + EP and 9 pts received T 240 mg/m2 + EP. T + EP was well tolerated. 2 pts at T 200 mg/m2 and 1 pt at T 240 mg/m2 experienced asymptomatic DLTs in cycle 1. 2 pts (1 at each dose) had an ANC < 1500 on cycle 2 day 1, delaying the start of cycle 2, and 1 pt at the T 200 mg/m2dose had grade 4 thrombocytopenia. There were no cases of febrile neutropenia or bleeding. PK analysis showed no drug interactions between T and EP. 17/19 pts were evaluable: 1 pt had CR, 14 had PR (confirmed ORR = 88%); 1 pt had SD (clinical benefit rate = 94%). Conclusions: In the Phase 1b part of the study, T + EP was well tolerated. Early activity results are promising with a confirmed objective response rate of 88%. This novel approach allowing the administration of chemotherapy while preserving HSPC and immune system function could potentially improve treatment outcomes for SCLC pts. Clinical trial information: NCT02499770.

Abstract P4-22-12: Ribociclib + fulvestrant in postmenopausal women with HR+, HER2– advanced breast cancer (ABC)

Abstract Background: Endocrine therapy (ET) is the treatment backbone for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC, but efficacy is limited by ET resistance. The cyclin-dependent kinase (CDK) 4/6–cyclin D (CCND1)–retinoblastoma (Rb) and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicated in ET resistance. CDK4/6 and PI3K/mTOR inhibitors act synergistically with ET in preclinical and clinical studies of HR+ breast cancer. Ribociclib (LEE011; CDK4/6 inhibitor) + fulvestrant ± alpelisib (BYL719) or buparlisib (BKM120) in HR+, HER2– ABC is being investigated in a Phase Ib/II study (NCT02088684). Here, we present results from the ribociclib + fulvestrant combination, with intermittent and continuous ribociclib dosing. Methods: Postmenopausal patients (pts) with HR+, HER2– ABC refractory to aromatase inhibitors received ribociclib intermittently (600 mg/day, 3-weeks-on/1-week-off; Arm A) or continuously (400 mg/day; Arm B; following Arm A safety evaluation) + fulvestrant (500 mg; Cycle 1 Day 1 and 15; subsequent cycles Day 1). Primary objective: dose-limiting toxicities (DLTs) to confirm the recommended Phase II dose of ribociclib + fulvestrant. Secondary objectives: safety, pharmacokinetics, and preliminary antitumor activity (RECIST v1.1); biomarkers that may correlate with response were also assessed. Results: As of March 10, 2016, 24 pts received ribociclib + fulvestrant (Arm A, n=13; Arm B, n=11); 4 pts in Arm B were ongoing; median duration of exposure was 7.4 (Arm A) and 4.5 (Arm B) months. Median number of prior regimens: 4 (Arm A) and 3 (Arm B). Treatment discontinuation (n; Arm A, Arm B) was due to disease progression (11, 4), physician decision (1, 2), and adverse events (AEs; 1, 1). DLTs in Cycle 1 (n; Arm A, Arm B) were Grade [G] 3 pulmonary embolism (1, 0) and G3 aspartate aminotransferase elevation (0, 1). The most common G3/4 drug-related AE (Arm A, Arm B) was neutropenia (62%, 36%); 5 pts had QTcF prolongation >60 ms (n; 4, 1). Common all-Grade drug-related AEs (>35% pts) n (%)Arm A (n=13)Arm B (n=11)Neutropenia10 (77)7 (64)Fatigue9 (69)3 (27)Nausea6 (46)5 (46)Anemia6 (46)0 (0)Reduced appetite5 (39)1 (9) Best overall responses (BORs; n; Arm A, Arm B): partial response (PR; 3, 1), stable disease (SD; 9, 6), and neither complete response nor progressive disease (NCRNPD; non-measurable disease; 1, 4). Overall response rate: 23% (Arm A) and 9% (Arm B); disease control rate (BOR of complete response, PR, SD, or NCRNPD): 100% in both arms. Next-generation sequencing data (n; Arm A, Arm B) were available for 16 pts (7, 9): 5 pts had CCND1 alterations (PR [1, 0], SD [2, 1], and NCRNPD [0, 1]); 11 pts had PIK3CA alterations (PR [1, 0], SD [3, 4], and NCRNPD [1, 2]); 2 of these pts had both CCND1 and PIK3CA alterations (SD [1, 0] and NCRNPD [0, 1]). Conclusions: Ribociclib + fulvestrant has a manageable safety profile and shows preliminary clinical activity in pretreated pts with HR+, HER2– ABC. Both ribociclib intermittent and continuous dosing schedules were well tolerated. Clinical responses were observed in tumors with and without CDK4/6–cyclin D–Rb and PI3K/mTOR pathway alterations. Citation Format: Tolaney SM, Forero-Torres A, Boni V, Bachelot T, Lu Y-S, Maur M, Fasolo A, Motta M, Pan C, Dobson J, Hewes B, Chin Lee S. Ribociclib + fulvestrant in postmenopausal women with HR+, HER2– advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-12.

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

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

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

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability of Pomalidomide + Low-Dose Dexamethasone in Patients with Relapsed or Refractory and Refractory Multiple Myeloma and Renal Impairment

Background: Pomalidomide (POM) is indicated for patients (pts) with relapsed or refractory multiple myeloma (RRMM) who received ≥ 2 prior therapies including lenalidomide and bortezomib and demonstrated progression on or within 60 days of completion of the last treatment (Tx). Renal impairment (RI) is a common comorbidity of multiple myeloma (MM) occurring in 20% to 40% of pts (Eleutherakis-Papaikovou, et al. Leuk Lymphom, 2007; Knudsen, et al., Eur J Haematol, 2000). POM is extensively metabolized, with < 5% eliminated renally as the parent drug (Hoffmann, et al., Cancer Chemother Pharmacol, 2013). POM in combination with low-dose dexamethasone (LoDEX) has shown efficacy in pts with RRMM and moderate RI (creatinine clearance [CrCl] < 30-44 mL/min), but pts with severe RI (CrCl < 30 mL/min; serum creatinine> 3 mg/dL) were excluded from most trials (Siegel, et al., Blood. 2012; Weisel, et al., J Clin Oncol, 2013). MM-008 is a multicenter, open-label, phase 1 study assessing the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function.Methods: Pts withRRMM (≥ 1 prior Tx) and normal kidney function or mild RI (creatinine clearance [CrCl] ≥ 60 mL/min; Cohort A—control arm), severe RI (CrCl < 30 mL/min) not requiring dialysis (Cohort B), and severe RI requiring dialysis (Cohort C) were eligible. Cohort A received POM 4 mg, and Cohort B received POM 2 or 4 mg on days 1-21 of a 28-day cycle, following a 3 + 3 dose-escalation design. Cohort B results informed the 4 mg dosing of Cohort C. All cohorts received DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Tx continued until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) were defined as any of the following: grade (Gr) 4 neutropenia, febrile neutropenia, Gr 4 thrombocytopenia that is a ≥ 30% decrease in platelets from baseline and requires > 1 platelet transfusion, Gr 3 thrombocytopenia with significant bleeding (requiring hospitalization and/or platelet transfusion), Gr 4 infection, or ≥ Gr 3 other non-hematologic toxicity related to POM. Serial plasma samples were analyzed to generate PK parameters. Updated PK and AE data for all cohorts will be presented.Results: As of July 17, 2014, updated data for 16 treated pts were available (8 in Cohort A; 3 in Cohort B at 2 mg; 4 in Cohort B at 4 mg; and 1 in Cohort C). Median age was 67 yrs (range, 46-76 yrs), 56% were male, all had Eastern Cooperative Oncology Group performance status 0 or 1, and a median time from diagnosis of 3.8 yrs (range, 0.6-12.5). No DLTs in cycle 1 were reported for any cohort. The most common Gr ≥ 3 adverse events (AEs) were neutropenia, anemia, infection, and fatigue (Table). Median relative dose intensity was consistent across cohorts: 90% (Cohort A), 90% (Cohort B; 2 mg), 100% (Cohort B; 4 mg) and 100% (Cohort C). Three pts discontinued due to AEs (2 in Cohort A and 1 in Cohort B 4 mg); no deaths have occurred during treatment phase.Conclusion: MM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with RRMM and severe RI. Preliminary PK data support mean dose-normalized exposure in pts with RRMM being similar between those with severe RI and those with no or mild RI at the clinical dose of 4 mg; early tolerability data (after one cycle) are encouraging.TableCohort A(n = 8)Cohort B(n = 3)Cohort B(n = 4)Cohort C(n = 1)Cohort CharacteristicsPOM dose4 mg2 mg4 mg4 mgCrCl (mL/min)≥ 60 mL/min< 30 mL/min without dialysis< 30 mL/min without dialysis< 30 mL/min with dialysisSafetyDose-limiting toxicities (n)N/A000Grade 3/4 AEs (n)Neutropenia4210Anemia3120Infection3200Fatigue2000N/A: Not applicable (4 mg POM is approved dose for population) DisclosuresMatous:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene Corp: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy. Harvey:Celgene Corp: Research Funding. Kasserra:Celgene Corp: Employment, Equity Ownership. Li:Celgene Corp: Employment, Equity Ownership. Chen:Celgene Corp: Employment. Doerr:Celgene Corporation: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Jacques:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Consultancy, Research Funding.

Phase I Trial of Sunitinib and Temsirolimus in Metastatic Renal Cell Carcinoma

BackgroundPreclinical data suggest that anti–vascular endothelial growth factor agents combined with mammalian target of rapamycin inhibitors yield synergistic antitumor effects. A phase I trial with a 3+3 dose escalation design of S with T was stopped after the first dose pair led to 2 of 3 patients experiencing dose-limiting toxicity (DLT). Patients and MethodsTo explore multiple potential dosing pairs of S and T, a 2-stage outcome-adaptive Bayesian dose-finding method was designed. The primary objective was to find the MTD of S and T in patients with advanced renal cell carcinoma. A 3-week treatment cycle consisted of daily S, 2 weeks of treatment, 1 week without treatment, and weekly T. ResultsTwenty patients received study drugs; the median number of previous therapies was 1. The number of patients (S and T doses in mg) was: 2 (S, 12.5; T, 6), 1 (S, 25; T, 12.5), 1 (S, 12.5; T, 8), 8 (S, 12.5 alternate 25; T, 9), 2 (S, 25; T, 6), 2 (S, 25 alternate 37.5; T, 6), 2 (S, 37.5; T, 6), and 2 (S, 37.5; T, 8). Six patients required dose reduction, 3 because of Grade 3 stomatitis, 2 because of Grade 3 thrombocytopenia; the mean number of cycles was 6.6 ± 5.3, the mean time during study was 159 ± 120 days. One patient experienced a DLT in cycle 1 and was nonevaluable, 1 had a partial response, 16 had stable disease, and 2 had progressive disease as best response. There were 21 Grade 3/4 adverse events but no treatment-related deaths. ConclusionThe MTD of S and T were not determined because of premature trial closure. S 37.5 mg/d, 2 weeks of treatment, 1 week with no treatment, and T 8 mg to 10 mg weekly are close to the MTD.

Abstract P4-16-11: Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors including breast cancer

Abstract Background: Afatinib, a potent irreversible ErbB Family Blocker, inhibits signaling from HER1, HER2 and HER4 dimers, and transphosphorylation of HER3. A Phase I trial was conducted to assess if afatinib 40 mg/day in combination with vinorelbine (VNR) 25 mg/m2 i.v. weekly could be safely administered to Japanese patients (pts). Patients and methods: The safety, tolerability and pharmacokinetics (PK) of daily oral afatinib plus weekly i.v. VNR in a 28-day cycle in Japanese pts was assessed using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose (MTD), based on dose-limiting toxicities (DLTs) in Cycle 1 (see Table; dose Levels 1 and 2). When the MTD was exceeded, dose Levels 2a and 3 allowed modifications of VNR dosing as used in clinical practice. Eligible pts were ≥20 years old with histologically confirmed refractory advanced/metastatic solid tumours, and an ECOG performance status (PS) 0-1. Adverse events (AEs) were documented as per NCI CTCAE v3.0. Response was assessed using RECIST 1.1, and PK parameters for both drugs were analyzed by intra-individual comparison, based on frequent blood sampling. Results: Seventeen pts were recruited. Median age was 60 (range 40-68) years, all pts had received previous chemotherapy, and 7/9 pts with BC had received HER2-targeted therapy. No DLTs were observed at dose Level 1. When 3/5 pts developed DLTs in Cycle 1 at an afatinib dose of 40 mg in Level 2 (see Table), an intermediate cohort 2a was introduced at 20 mg/m2 VNR i.v. weekly. Tolerability at Level 2a was confirmed. With afatinib dose modification permitted, and VNR dose skipping allowed for ANC &amp;lt;1500/mm3, dose re-escalation to VNR 25mg/m2 i.v. weekly at Level 3 was performed to establish a recommended phase II dose. At Level 3, 7/24 planned doses of VNR were skipped due to Grade 2 and 3 neutropenia, not qualifying as DLTs. One DLT occurred in a pt with Grade 2 epigastralgia in Course 1, who required afatinib dose reduction. Overall, the most frequent drug-related AEs were leukopenia, neutropenia (100% each), diarrhea (94%), anemia (70%), stomatitis (64%) and rash (41%). Nine BC pts were treated in cohorts 2a and 3, and all experienced diarrhea, leukopenia and neutropenia. No PK drug-drug interactions between afatinib and VNR were observed. Safety and PK profiles did not appear to differ between Japanese pts and Caucasian pts in a previous Phase I study. Two pts with BC and prior trastuzumab treatment had partial responses. Tumor shrinkage was observed in four of six evaluable BC pts, but not in other tumor types. Conclusions: Afatinib 40 mg/day plus vinorelbine 25 mg/m2/week was tolerable and showed early signs of clinical activity in Japanese pts. AEs were as expected and were managed by dose modifications of both compounds. Final data will be presented at this congress. Dose LevelsAfatinibVinorelbineN treatedDLTs (n)120 mg/day25 mg/m2/week3None240 mg/day25 mg/m2/week5Grade 4 neutropenia for 7 days (1); Grade 3 febrile neutropenia (1); Grade 3 pharyngeal infection with Grade 4 lipase and amylase elevations (1)2a40 mg/day20 mg/m2/week3 (all BC)None340 mg/day25 mg/m2/week6 (all BC)Grade 2 epigastralgia (1) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-11.

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability Of Pomalidomide + Low-Dose Dexamethasone In Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment

BackgroundPomalidomide (POM) is indicated for patients (pts) with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Renal impairment (RI) is a common comorbidity in multiple myeloma (MM), occurring in > 40% of pts. POM is extensively metabolized, with < 5% eliminated renally as the parent drug. Thus, renal function may not substantively affect exposure of the active parent compound. POM + low-dose dexamethasone (LoDEX) has shown efficacy in pts with relapsed/refractory MM (RRMM) with moderate RI in phase 2 and phase 3 trials. However, pts with severe RI were excluded from these trials. MM-008 is an active multicenter, open-label, phase 1 study designed to prospectively assess the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function. MethodsPts with RRMM and ≥ 1 prior therapy were eligible for enrollment. Pts in Cohort A (creatinine clearance [CrCL] ≥ 60 mL/min) served as the control population and received POM 4 mg on days 1-21 of each 28-day cycle. Pts in Cohort B (CrCL < 30 mL/min but not requiring dialysis) followed a standard 3 + 3 dose-escalation design, receiving POM 2 mg on days 1-21 of each 28-day cycle and based on results, escalating to 4 mg. Dosing for Cohort C (CrCL < 30 mL/min and requiring dialysis) was informed by the results from Cohort B. All cohorts received dexamethasone 40 mg (20 mg for pts aged > 75 years) on days 1, 8, 15, and 22. Pts were not permitted to enroll in more than 1 cohort. Granulocyte colony-stimulating factor for management of neutropenia was not permitted in cycle 1, but could be started on day 1 of the next cycle at the physician's discretion. Treatment was continued until disease progression or unacceptable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (V 4.0). PK samples were obtained pre- and post-POM dose on days 1, 2, and 3 (after single doses) and days 21, 22, and 23 (after multiple doses) of cycle 1 for cohorts A and B. PK data were dose-normalized for comparison across cohorts by dividing the measured exposure by the POM dose in milligrams. ResultsAs of April 1, 2013, 11 pts have been treated (8 in Cohort A; 3 in Cohort B at 2 mg). At screening, median age (range) was 68 years (46-71 years) and 64 years (57-64 years) while median CrCL (range) was 85 mL/min (53.1- 114.8 mL/min) and 18.4 mL/min (12.5-25.7 mL/min) in cohorts A and B, respectively. The most common grade ≥ 3 adverse events were neutropenia (Cohort A: 4 pts; Cohort B: 1 pt), infections (Cohort A: 2 pts; Cohort B: 2 pts), and anemia (Cohort A: 2 pts; Cohort B: 1 pt). No dose-limiting toxicities in cycle 1 have been reported. Median duration of treatment and relative dose intensity were similar between cohorts A and B, 4.1 months (range, 1.8-5.1 months) vs 3.9 months (range, 1.8-8.5 months) and 1.0 (range, 0.5-1.1) and 1.1 (range, 1.0-1.1), respectively. Only 1 pt (Cohort A) discontinued treatment due to adverse events. Five pts remain on study (Cohort A: 3 pts; Cohort B: 2 pts). Initial PK analyses showed that mean dose-normalized AUC024in Cohort B was approximately 20% lower than in Cohort A. Mean dose-normalized Cmax in Cohort B was approximately 30% lower than that in Cohort A after a single dose but comparable after multiple doses. Based on these results, additional pts in Cohort B and pts in Cohort C will receive POM 4 mg. Updated PK and adverse event data will be presented at the meeting. ConclusionMM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with severe RI. Preliminary data suggest that dose-normalized exposure in pts with RRMM with severe RI is similar to that in pts with normal to mildly impaired renal function. No dose-limiting toxicities have been reported, and early tolerability data are encouraging. Disclosures:Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Approved in the US but not in Europe. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Kasserra:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Doerr:Celgene: Employment, Equity Ownership. Sternas:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Shah:Celgene: Consultancy, Research Funding.

A Phase I/II Trial Of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) In Patients With Newly Diagnosed Multiple Myeloma: Final Results Of MTD Expansion Cohort

BackgroundCarfilzomib is a proteasome inhibitor that irreversibly binds its target and has been validated as both relapse and upfront therapies for multiple myeloma. To optimize pre transplant response, we combined carfilzomib with the widely accessible backbone of cyclophosphamide-thalidomide-dexamethasone (CTD). We previously reported results of the Phase I component of the trial (in which no MTD was reached); we now report results for the MTD and fully accrued expansion cohorts at the MTD of the CYCLONE trial NCT01057225. MethodsNewly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with carfilzomib IV Days 1,2,8,9,15,16 (see Table below for dosing per cohort) along with cyclophosphamide 300 mg/m2 PO Days 1,8,15, thalidomide 100 mg PO Days 1-28 and dexamethasone 40 mg PO Days 1,8,15,22. The initial phase I/ II regimen is shown below – as no DLTs were observed, we increased dosing of carfilzomib to 36 and then 45mg/m2 and have now nearly fully accrued to the Phase II dose level +1 (27mg/m2) and expansion MTD (36mg/m2). Treatment was for 4 cycles with planned SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. ResultsA total of 54 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II (CFZ 27mg/m2), and 27 at CFZ 36-45mg/m2. Median age was 63 (range 27-77) and 52% were male. ISS Stage was advanced (II-III) in 57% The overall partial response rate or better following 4 cycles of CYCLONE at dose level 0 or greater is 91%: CR 18%, VGPR 58%, PR 16%, MR 2%, SD 4%. One patient withdrew from the trial after cycle 1.At dose level 2, 3/7 patients experienced dose-limiting toxicity in cycle 1 including: grade 3 alanine aminotransferase increase (possibly related); grade 3 infusion reaction (probably related); and grade 4 heart failure with grade 3 dyspnea, atrial fibrillation, and fatigue (all possibly related). No dose-limiting toxicity was observed in 6 patients at dose level 1 and thus DL1 was deemed the MTD.Across dose levels, adverse events are fully evaluable in 48 patients. AEs of grade 3 or higher at least possibly related to CYCLONE occurred in 26 (54%) – 35% non hematological and 33% hematological. Most commonly reported non hematological toxicities (all grades) included fatigue (63%), constipation (46%), elevated creatinine (27%), hyperglycemia (27%), lethargy (25%) peripheral sensory neuropathy (25% - all grade 1), and somnolence (21%); however, grade 3/4 toxicities occurring in >5% were uncommon: hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%). Three cases of pneumonia required hospitalization. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included lymphopenia (23%) and neutropenia (17%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. 90% completed at least 4 cycles.With median follow-up of 16 months (range 0-64), 1-year PFS was 90% and 1-year OS was 98%. ConclusionThe 4 drug CYCLONE regimen is highly efficacious with an overall response rate after only 4 cycles of 91% (76% ≥VGPR) at the dosing level of carfilzomib IV 20/27-36 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. CYCLONE is a combination that results in rapid and deep responses with minimal neuropathy prior to stem cell transplant. Comparative studies of this regimen with longer duration of therapy (as induction or consolidation) at the defined MTD should be considered. Disclosures:Mikhael:Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Reeder:Millenium: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Costa:Otsuka: Research Funding. Stewart:Celgene: Honoraria; Millenium: Honoraria, Research Funding; Onyx: Research Funding.

Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity.