Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Abstract This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

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A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

Investigational New Drugs ◽

10.1007/s10637-020-01056-4 ◽

2021 ◽

Author(s):

Alexey V. Danilov ◽

Stephen E. Spurgeon ◽

Tanya Siddiqi ◽

Anne-Marie Quinson ◽

Daniela Maier ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Residual Disease ◽

Transmembrane Protein ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Lymphocytic Leukemia ◽

Open Label ◽

Dose Escalation Study ◽

Phase Ib

SummaryBI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.

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Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440)

Haematologica ◽

10.3324/haematol.2020.261107 ◽

2020 ◽

pp. 0-0

Author(s):

Stephan Stilgenbauer ◽

Franck Morschhauser ◽

Clemens-Martin Wendtner ◽

Guillaume Cartron ◽

Michael Hallek ◽

...

Keyword(s):

Overall Response Rate ◽

Dose Schedule ◽

Maximum Tolerated Dose ◽

Lymphocytic Leukemia ◽

Dose Finding ◽

First Line ◽

Open Label ◽

Open Label Phase ◽

Phase 1B ◽

Grade 3

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100–400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3–4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3–4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.

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Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2018-05-853564 ◽

2018 ◽

Vol 132 (15) ◽

pp. 1568-1572 ◽

Cited By ~ 61

Author(s):

Kerry A. Rogers ◽

Ying Huang ◽

Amy S. Ruppert ◽

Farrukh T. Awan ◽

Nyla A. Heerema ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Tumor Lysis Syndrome ◽

Lymphocytic Leukemia ◽

Tumor Lysis ◽

Key Points ◽

Phase 1B

Key Points Cytoreduction with obinutuzumab and ibrutinib followed by the addition of venetoclax has acceptable safety with no tumor lysis syndrome. This combination has preliminary activity including complete remissions with undetectable residual disease in relapsed or refractory CLL.

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Venetoclax plus Dose-Adjusted R-EPOCH (VR-EPOCH) for Richter's Syndrome

Blood ◽

10.1182/blood.2021011386 ◽

2021 ◽

Author(s):

Matthew S. Davids ◽

Kerry A. Rogers ◽

Svitlana Tyekucheva ◽

Zixu Wang ◽

Samantha Pazienza ◽

...

Keyword(s):

Cellular Therapy ◽

Residual Disease ◽

Tumor Lysis Syndrome ◽

Progression Free Survival ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Phase 2 Trial ◽

Grade 3 ◽

Richter’S Syndrome

Richter's Syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. (Funded by Genentech/AbbVie; ClinicalTrials.gov number, NCT03054896).

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Ibrutinib plus obinutuzumab as frontline therapy for chronic lymphocytic leukemia is associated with a lower rate of infusion-related reactions and with sustained remissions after ibrutinib discontinuation: a single-arm, open-label, phase 1b/2 clinical trial NCT0231576

10.21203/rs.3.rs-887972/v1 ◽

2021 ◽

Author(s):

Januario E. Castro ◽

Paula A. Lengerke-Diaz ◽

Juliana Velez-Lujan ◽

Michale Y. Choi ◽

Eider F. Moreno-Cortes ◽

...

Keyword(s):

Residual Disease ◽

Single Agent ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Open Label ◽

Continuous Administration ◽

Open Label Phase ◽

Phase 1B ◽

Treatment Safety ◽

Anti Cd20

Abstract Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials.

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Randomized Comparison of Cladribine with Cyclophosphamide and Fludarabine with Cyclophosphamide in Previously Untreated Progressive and Symptomatic Chronic Lymphocytic Leukemia: The Interim Analysis of PALG CLL3 Trial.

Blood ◽

10.1182/blood.v106.11.2121.2121 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2121-2121 ◽

Cited By ~ 1

Author(s):

Tadeusz Robak ◽

Jerzy Z. Blonski ◽

Joanna Gora-Tybor ◽

Jacek Najda ◽

Beata Stella-Holowiecka ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Interim Analysis ◽

Residual Disease ◽

Complete Response ◽

Similar Efficacy ◽

Lymphocytic Leukemia ◽

P Value ◽

Grade 3 ◽

Toxicity Criteria ◽

Related Mortality

Abstract The efficacy and toxicity of cladribine (2-CdA) + cyclophsphamide (CY) - CC versus fludarabine (FA) + CY - FC were compared in previously untreated chronic lymphocytic leukemia (CLL) patients. The study was started in January 2004. Eligible patients were asigned to either 2-CdA 0,12mg/kg/d and CY 250mg/m2/d for 3 consecutive days or FA 25mg/m2/d and CY 250mg/m2/d also for 3 days. Courses were repeated at 28 days intervals or longer if myelosupression and/or infection developes for a maximum 6 courses. The response and toxicity criteria were those recommended by NCI SWG. Minimal residual disease (MRD) was evaluated by flow cytometry if complete response (CR) was achieved. As shown in the table, there were no significant differences in the rates of overall response (OR), CR, grade 3/4 thrombocytopenia, neutropenia and infections between the programmes. MRD negativity was obtained in 4 patients in CC arm and in 6 patients in FC arm (p=0.69). The death rate was similar in both groups, 2 (3.2%) and 6 (8.2%), respectively (p=0.19). The therapy related mortality was not observed. In conclusion, CC and FC programmes seem to have similar efficacy and toxicity in previously untreated CLL patients. The results of the interim analysis of PALG CLL3 trial justify continuation of this study. Treatment Pts enrolled Pts evaluated OR (%) CR (%) Thrombocytopenia Neutropenia Infections CC 96 63 57 (90.5) 20 (31.7) 8 (12.7) 15 (23.8) 26 (41.3) FC 100 73 62 (84.9) 25 (34.3) 6 (8.2) 17 (23.3) 20 (27.4) p value 0.24 0.45 0.27 0.53 0.06

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An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2011-05-351833 ◽

2011 ◽

Vol 118 (15) ◽

pp. 4079-4085 ◽

Cited By ~ 19

Author(s):

Marco Montillo ◽

Alessandra Tedeschi ◽

Valeria Belsito Petrizzi ◽

Francesca Ricci ◽

Monica Crugnola ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Opportunistic Infections ◽

Residual Disease ◽

Complete Response ◽

Primary Objective ◽

Common Adverse Event ◽

Lymphocytic Leukemia ◽

Open Label ◽

Antibody Treatment ◽

Synergistic Cytotoxicity

Abstract Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52+ B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m2 per day, oral cyclophosphamide 250 mg/m2 per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.

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Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Blood ◽

10.1182/blood-2018-11-880526 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1964-1976 ◽

Cited By ~ 38

Author(s):

Andrew D. Zelenetz ◽

Gilles Salles ◽

Kylie D. Mason ◽

Carla Casulo ◽

Steven Le Gouill ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Phase 2 ◽

Non Hodgkin Lymphoma ◽

Phase 1B ◽

Grade 3

Abstract Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

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A Phase Ib/II Study of Combined Obinutuzumab and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v126.23.4160.4160 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4160-4160

Author(s):

Januario E. Castro ◽

Michael Y. Choi ◽

Carlos I. Amaya-Chanaga ◽

Natalie Nguyen ◽

Amine Ale-Ali ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

High Dose ◽

Open Label ◽

Therapy Discontinuation ◽

Phase Ib ◽

Grade 3 ◽

Anti Cd20

Abstract Chronic lymphocytic leukemia (CLL) is not curable and ultimately patients (pts) relapse and require additional treatment. In addition, most of CLL pts are older than 65 years old or are unfit to receive chemotherapy. Because of these reasons there is a need for the development of novel therapeutic strategies. Obinutuzumab, a third-generation anti-CD20 mAb, in combination with chlorambucil is currently approved by the FDA for previously untreated pts. Studies have demonstrated that most of the clinical benefit of this regimen is derived from obinutuzumab rather than chlorambucil, and also that obinutuzumab has superior clinical activity than rituximab. Because of these and our previous clinical studies that have shown synergism between HDMP and anti-CD20 antibodies, we initiated an open label phase Ib/II clinical study of obinutuzumab with HDMP for therapy of pts with CLL. The study is divided in two cohorts of 20 pts each, front-line (FL) and relapsed / refractory (RR) CLL. Pts receive HDMP 1g/m2 on Day 1-3 of cycles 1-4 (28 days / cycle) and obinutuzumab administered based on FDA dosing recommendations for 6 cycles. All pts received prophylactic medications (trimethoprim/sulfamethoxazole, acyclovir, fluconazole and allopurinol). 85% of target accrual has been completed (RR cohort=19 pts; FL cohort=15 pts). Here we present a preliminary analysis of safety /tolerability of this regimen. The median age in the RR cohort was 68 years +/- 7.8 and 62 years +/- 7.3 in the FL cohort. 84% and 87% of the pts in the RR and FL cohorts had a CIRS > 6, respectively. The median baseline absolute lymphocyte count was 32.9 +/- 32.6 x103/mm3 for pts in the RR cohort and 49.3 +/- 98.1 x103/mm3 for pts in the FL cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 32% RR vs. 0% FL, del(13q) in 63% RR vs.67% FL, del(11q) in 21% RR vs. 33% FL, and trisomy 12 in 16% RR vs. 20% FL. All 34 pts were assessed for adverse events (AEs). Most AEs were grade 1-2 (RR=88%; FL=92%) without development of dose-limiting toxicities (DLTs). One pt in the RR cohort developed asymptomatic metformin-associated lactic acidosis that required overnight inpatient observation without therapy discontinuation. Grade 1-2 obinutuzumab-infusion-related reactions (IRR) were observed in 42% and 87% of pts in the RR and FL cohort, respectively. We did not observe grade 3-4 IRR. Only one patient has required therapy discontinuation due to asymptomatic GI bleeding that required blood transfusion and resolved spontaneously. We observed neutropenia (RR: all grades: 63%, grade 3-4: 26%; FL: all grades: 53%, grade 3-4: 33%), thrombocytopenia (RR: all grades: 68%, grade 3-4: 37%; FL: all grades: 80%, grade 3-4: 40%) and anemia (RR: all grades: 58%; FL: all grades: 53%). There were no cases of febrile neutropenia. Three pts (16%) in the RR cohort developed community-acquired pneumonia, requiring outpatient treatment with oral antibiotics but not study treatment discontinuation. The most frequent non-hematological AEs were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). All 34 pts have had favorable clinical and hematological responses. Six pts (4 pts in the RR cohort and 2 pts in the FL cohort) were evaluable for response assessment by iwCLL criteria. The four pts in the RR cohort achieved a PR. In the FL cohort, 1 pt achieved a CR MRDneg (<0.01% CLL in the marrow), and the other pt achieved a PR. Overall, obinutuzumab with HDMP has been well tolerated with no evidence of DLTs. The profile of AEs appears favorable compared to those noted with obinutuzumab in combination with chlorambucil, particularly in terms of grade 3-4 IRR (0% vs 20%) or rate of therapy discontinuation (3% vs 7%). Enrollment continues and updated information will be presented during the meeting. Disclosures Choi: AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

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A phase IB, open label, safety and pharmacokinetic (PK) study of escalating doses of PTK787/ZK 222584 (PTK/ZK) in combination with paclitaxel and carboplatin in patients (Pts) with stage IC to IV epithelial ovarian cancer (EOC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5075 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5075-5075 ◽

Cited By ~ 1

Author(s):

W. Schroder ◽

M. Campone ◽

S. Abadie ◽

P. Witteveen ◽

P. Viens ◽

...

Keyword(s):

Residual Disease ◽

Systemic Exposure ◽

Maximum Tolerated Dose ◽

Open Label ◽

Dose Escalation Study ◽

Phase Ib ◽

First Line Therapy ◽

Pre Treatment ◽

Tumor Growth And Metastasis ◽

Grade 3

5075 Background: Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) are important mediators of tumor growth and metastasis and their expression is associated with poor prognosis in EOC. PTK/ZK is a novel, oral, angiogenesis and lymphangiogenesis inhibitor that blocks tyrosine kinase signaling from all known VEGFRs. Methods: An open label, multicenter, phase IB dose escalation study evaluating PTK/ZK with chemotherapy as first line therapy in Pts with stage IC to IV EOC. Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of PTK/ZK were assessed; PK of PTK/ZK, carboplatin and paclitaxel was characterized. Paclitaxel was administered as a 3-hour infusion on day 1 of each 21-day cycle at a dose of 175 mg/m2. Carboplatin was given immediately after paclitaxel as a 30-min IV infusion to AUC of 5 mg min/mL. PTK/ZK was given once daily from day 3 to day 21 of each chemotherapy cycle. Cohorts of 3 to 6 Pts received doses of PTK/ZK at 250, 500, 750, 1000 or 1250 mg/day. Dose expansion in 21 additional Pts was conducted with 1250 mg/day without reaching MTD. After completion of chemotherapy, PTK/ZK was given continuously until disease progression. PK samples were collected in cycle 1 (without PTK/ZK) and cycle 2 (after PTK/ZK pre-treatment). Results: 42 Pts were enrolled. To date 39 Pts are evaluated for safety, 19 Pts for DLT, 35 Pts for PK and 21 Pts with residual disease for tumor response. No DLTs were reported. The most frequently observed grade 3/4 toxicity was neutropenia (31%), leucopenia (18%) and hypertension (10%). PTK/ZK did not aggravate chemotherapy related side effects. To date 67% of Pts had achieved CR/PR, 9% SD, 5% PD and 19% UNK. PTK/ZK exposure at steady state was similar in cycle 1 and 2. PTK/ZK had no impact on the systemic exposure of carboplatin. Paclitaxel exposure was decreased by an average of 18% in cycle 2 compared to cycle 1 for Pts treated with PTK/ZK 1250 mg/day. Conclusion: Combination of PTK/ZK with paclitaxel and carboplatin is feasible and shows favorable safety profile. The combination is active in EOC and deserves further evaluation. [Table: see text]

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