- Domenica Lorusso (Milan, Italy)
- Ana Oaknin (Barcelona, Spain)
LBA58 - BAROCCO: A randomized phase II study of weekly paclitaxel vs cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC) (ID 2560)
- Nicoletta Colombo (Milan, Italy)
Abstract
Background
Hypoxia induced by antiangiogenic agents could cause a functional impairment of homologous recombination, thus sensitizing wild-type (wt) BRCA tumor cells to PARP inhibition. In a phase II study the combination of cediranib-olaparib increased progression free survival (PFS) in women with recurrent platinum sensitive OC with respect to olaparib.
Methods
123 patients were allocated in a 1:1:1 ratio to receive: 80 mg/m2 weekly paclitaxel up to 24 weeks (control), olaparib 600 mg tablet (300 mg twice daily) together with 20 mg cediranib daily (continuous schedule) or 20 mg cediranib given 5 days/week (intermittent schedule) until progression. PFS comparison between experimental schedules and the control arm (alpha one-sided 5%; power 80% to detect a HR of 0.5) was the primary objective.
Results
Median platinum-free interval was 1.8 mos, 59% of patients were pretreated with >3 chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.7, and 3.8 mos. Estimated HR for PFS in continuous arm vs control was 0.76 (90% CI: 0.49-1.17), p = 0.28 by log-rank test. HR for PFS in intermittent arm vs. control was 1.08 (90% CI: 0.71-1.64), p = 0.76 by log-rank test. In the subgroup gBRCA wt (n = 109) the median PFS for paclitaxel, the continuous, and the intermittent schedules were 2.1, 5.8 and 3.8 mos and HR for PFS in continuous arm vs control was 0.63 (95% CI: 0.36 to 1.10; p = 0.10). The toxicity profile of the study arms was as expected and similar between experimental arms. 11%, 18%, and 7% in control, continuous and intermittent arm discontinued treatment for adverse events. Five serious adverse drug reactions occurred and two of these were fatal: one in the control and one in the continuous arm.
Conclusions
The combination of cediranib and olaparib is effective in heavily pretreated PROC patients with the advantage of an oral administration and good tolerability. The continuous schedule of cediranib-olaparib showed a promising trend towards improved PFS in comparison with weekly paclitaxel particularly in the BRCA wt population.
Clinical trial identification
IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.
Legal entity responsible for the study
Istituto di Ricerche Farmacologiche Mario Negri IRCCS.
Funding
AstraZeneca.
Disclosure
N. Colombo: Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: PharmaMar; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: BioCad; Advisory / Consultancy: Takeda. G. Tognon: Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Tesaro. M. Ratti: Travel / Accommodation / Expenses: Tesaro Bio. All other authors have declared no conflicts of interest.
LBA59 - Phase Ib/II study of AVB500 (high affinity inhibitor of GAS6/AXL path) in combination with PAC and PLD in platinum resistant recurrent ovarian cancer (ID 6602)
- Bradley J. Monk (Arizona, United States of America)
Abstract
Background
AXL/GAS6 pathway has been implicated in disease progression and chemotherapy resistance in platinum-resistant ovarian cancer (PROC), where response to standard of care chemotherapy in patients is typically 10-15% [Gynecologic Oncology 133 (2014) 624–631]. AVB500’s safety profile allowed the initial clinical study to be conducted in healthy volunteers (NCT03401528) and a proprietary pharmacodynamic assay (serum GAS6) identified pharmacologically active doses. Rather than traditional cancer therapeutic dose selection using an MTD, PK/PD modeling was used to select a human dose targeting specific levels of GAS6 suppression in cancer patients. That AVB500 dose (10mg/kg) is now being investigated in a P1b/P2 PROC study (NCT03639246) in patients who received 1 to 3 prior lines of therapy. The safety, PK, PD and response rate via RECIST v1.1 from the initial cohort in the P1b Recurrent PROC trial are presented.
Methods
The phase 1b safety lead-in portion of the study enrolled patients into two cohorts to investigate the combination of AVB500 with pegylated liposomal doxorubicin (PLD) or paclitaxel (PAC). The primary objectives were to assess safety and tolerability of the combinations and to confirm the RP2D. Secondary endpoints included effects on serum GAS6 and preliminary anti-tumor efficacy measures.
Results
The data from the initial cohorts of patients (N = 12; 6 patients in each cohort) demonstrated full suppression of serum GAS6 confirming the RP2D. AVB500 was safe and well-tolerated in combination with PLD and PAC. There were no serious adverse events. Efficacy data show early proof of concept with overall best response rate (ORR)2 by Investigator determined RECIST v1.1 criteria: Partial responses (PR) in 5 out of 12 patients (41.7%; 95% CI [15.2, 72.3]) Three responders had at least 60% tumor regression Two responders had more than 80% regression Clinical benefit rate (PR+SD) of 58%
Conclusions
The current data provide early clinical proof of concept for anti-tumor activity of GAS6 inhibition in PROC (41.7%) when compared to historical data for SOC alone (10-15%). Given the safety profile and early evidence of anti-tumor activity, the AVB500 risk/benefit profile for this drug is compelling.
Clinical trial identification
NCT03639246.
Legal entity responsible for the study
Aravive Inc.
Funding
Aravive, Inc.
Disclosure
B.J. Monk: Advisory / Consultancy: Aravive. R.L. Coleman: Advisory / Consultancy: Aravive. K.N. Moore: Advisory / Consultancy: Aravive. K.C. Fuh: Advisory / Consultancy, Licensing / Royalties: Aravive. L. Bonifacio: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Aravive. G. McIntyre: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Aravive. D. Prohaska: Shareholder / Stockholder / Stock options, Full / Part-time employment: Aravive. A. Giaccia: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Aravive. M.J. Baker: Shareholder / Stockholder / Stock options, Full / Part-time employment: Aravive. R. Tabibiazar: Shareholder / Stockholder / Stock options, Officer / Board of Directors: Aravive. M.A. Bookman: Advisory / Consultancy: Aravive.
Invited Discussant LBA58 and LBA59 (ID 6751)
- Antonio González Martín (Madrid, Spain)
LBA60 - Randomized phase II (RP2) study of ATR inhibitor M6620 in combination with gemcitabine versus gemcitabine alone in platinum-resistant high grade serous ovarian cancer (HGSOC) (ID 1547)
- Panagiotis A. Konstantinopoulos (Boston, United States of America)
Abstract
Background
HGSOCs exhibit genomic instability and high replication stress due to universal loss of the G1/S checkpoint (via TP53 mutations), presence of homologous recombination alterations and induction via amplification of MYC and CCNE1 oncogenes. Based on in vitro and in vivo data, we hypothesized that addition of the selective ATR inhibitor M6620 to gemcitabine (gem) would demonstrate acceptable toxicity and superior efficacy in HGSOC.
Methods
We conducted a multicenter, open-label, RP2 study of gem/M6620 versus gem alone (1:1 randomization) in platinum resistant HGSOC. Randomization was stratified based on platinum free interval (PFI), (PFI≤3 months vs > 3 months). Primary endpoint was progression-free survival (PFS) while secondary endpoints included safety, objective response and clinical benefit rate. Unlimited prior lines but ≤1 prior regimen in the platinum resistant setting were allowed. Patients (pts) received gem 1000 mg/m2 IV on Days 1 and 8 with or without M6620 210 mg/m2 IV on Days 2 and 9 of a 21-day cycle until disease progression (PD) or intolerable toxicity. Pts on gem alone were allowed to crossover to gem/M6620 only if they developed PD by RECIST. In order to have 80% power to detect improvement of median PFS from 15 weeks with gem to 27.3 weeks with gem/M6620 (hazard ratio (HR) =0.55) with a one-sided alpha level of 0.1, 64 total pts were required.
Results
70 pts were randomized, 36 to gem and 34 to gem/M6620 arms. Kaplan-Meier estimated median PFS was 14.7 weeks in the gem alone versus 22.9 weeks in the gem/M6620 arm; gem/M6620 HR was 0.57 (90% CI, 0.33-0.997; 1-sided log-rank test p = 0.047). The benefit of addition of M6620 was observed mainly among pts stratified into the PFI≤3 months group (HR = 0.31; 90% CI, 0.13-0.77; 1-sided p = 0.013); insignificant PFS difference between the two arms was observed among pts with PFI>3 months (HR = 0.95; 90% CI, 0.46-1.97; 1-sided p = 0.45). No increase in treatment-related toxic effects was observed in the gem/M6620 arm.
Conclusions
Addition of the ATR inhibitor M6620 to gem in platinum resistant HGSOC met the primary endpoint of this RP2 trial without increasing toxicity. Further evaluation of gem/M6620 in this setting is warranted.
Clinical trial identification
NCI CTEP: 9944; NCT02595892.
Legal entity responsible for the study
National Cancer Institute (NCI).
Funding
National Cancer Institute (NCI).
Disclosure
P.A. Konstantinopoulos: Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Advisory Board: Vertex; Advisory / Consultancy, Advisory Board: Pfizer; Research grant / Funding (institution): Eli Lilly. R.T. Penson: Advisory / Consultancy, Advisory Board: AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Eisai; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck & Co; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Genentech/Roche; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi Aventis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Vascular Biogenics; Advisory / Consultancy, Advisory Board: Sutro Biopharma; Advisory / Consultancy, Advisory Board: Mersana Therapeutics; Research grant / Funding (institution): Array Biopharma. L.R. Duska: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline/Novartis; Research grant / Funding (institution): Morab; Honoraria (self), Research grant / Funding (institution): MorphoTek; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Aduro BioTech; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Ludwig; Research grant / Funding (institution): LEAP Therapeutics; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Inovio; Advisory / Consultancy: Cue Biopharma; Research grant / Funding (institution): Advaxis. M.A. Crispens: Advisory / Consultancy: AbbVie; Research grant / Funding (institution): AstraZeneca. A.B. Olawaiye: Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Advisory Board: Tesaro. M.T. McHale: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Verastem. R.J. Schilder: Advisory / Consultancy, Consultant: Incyte; Advisory / Consultancy, Consultant: Immunogen; Advisory / Consultancy, Consultant: Celsion; Advisory / Consultancy, Consultant: Flatiron. G.I. Shapiro: Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck KGaA/EMD-Serono; Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Sierra Oncology; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: Bicycle Therapeutics; Advisory / Consultancy: Fusion Pharmaceuticals; Advisory / Consultancy: Cybrexa Therapeutics; Advisory / Consultancy: Astex; Advisory / Consultancy: Almac; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Angiex; Advisory / Consultancy: Daiichi Sankyo; Research grant / Funding (institution): Array Biopharma. U.A. Matulonis: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Myriad Genetics; Advisory / Consultancy: Clovis; Advisory / Consultancy: Merck; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Mersana; Advisory / Consultancy: Geneos; Advisory / Consultancy: Fuji Firm; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Cerulean; Advisory / Consultancy: 2X Oncology. All other authors have declared no conflicts of interest.
993O - OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel+/- novel agents in platinum-resistant ovarian cancer: Vistusertib (ID 5130)
- Susana Banerjee (London, United Kingdom)
Abstract
Background
OCTOPUS, an NCRI investigator-initiated umbrella phase II trial, tests the addition of targeted agents to weekly paclitaxel (wP) in recurrent platinum-resistant/refractory ovarian cancer. The first agent tested is the dual mTORC1/mTORC2 inhibitor vistusertib (V). Preclinical studies support targeting PI3K/AKT/mTOR signalling. The combination of V and wP showed activity in ovarian high grade serous carcinoma (HGSC) in phase I. This is the first randomised trial of wP and dual mTORC1/2 inhibition in ovarian cancer.
Methods
In this double-blind trial, patients with platinum-resistant/refractory HGSC were randomised 1:1 to wP (80mg/m2 D1, D8, D15 of 28 day cycle) + oral V (50mg BD) or placebo (P) (D1-3, D8-10, D15-17). The primary endpoint is progression-free survival (PFS) (RECIST v1.1/GCIG CA125 criteria) and response is a key secondary end-point. A mandatory pre-treatment biopsy (if technically feasible), archival tumour tissue and serial blood samples were collected. The study uses a 3-outcome approach: significance at 10% (1-sided) for PFS indicates activity, significance at 20% also requires evidence of an improvement in response. The study has 90% power to detect a hazard ratio (HR) of 0.67.
Results
140 patients were randomised; median age 63 (range: 36-86); 18% platinum-refractory; 54% had ≥3 prior therapy; 7% had prior taxane in previous 6 months (m); 66% had an image-guided biopsy at study entry. Median PFS was 4.5 vs 4.2m (HR 0.84; 80% CI 0.67 to 1.07; 1-sided p = 0.18); median OS was 9.7 vs 11.1m (HR 1.21, 80% CI 0.91 to 1.60; p = 0.80); RR (RECIST/GCIG CA125: CR+PR) was 53% vs 56% for wP+V vs wP+P respectively. Grade 3/4 adverse events were 24 vs 25%. There was significantly more gastro-oesophageal reflux (grd 1/2 10 v 0%), rash (grd 2/3 9 v 0%) and lymphopenia (grd 2/3/4 47 v 31%) on wP+V. Ongoing translational research exploring the influence of PI3K/mTOR signalling on platinum resistance and response to wP will be presented.
Conclusions
There was modest evidence of improvement in PFS with the addition of V, but this was not supported by response or OS. Translational research and subgroup analyses are ongoing.
Clinical trial identification
ISRCTN16426935.
Legal entity responsible for the study
NHS Greater Glasgow and Clyde/University of Glasgow.
Funding
AstraZeneca.
Disclosure
S. Banerjee: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self): Roche; Honoraria (self): Merck; Travel / Accommodation / Expenses: Nucana; Honoraria (self): Immunogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Advisory / Consultancy: Gamamabs. A.R. Clamp: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Clovis. J. krell: Honoraria (self), Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): Takeda. R.M. Glasspool: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Immunogen; Honoraria (self), Advisory / Consultancy: Sotio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Lilly/Ignyta; Travel / Accommodation / Expenses: Roche. C. Orbegoso: Full / Part-time employment: AstraZeneca. C. Gourley: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Honoraria (self), Advisory / Consultancy: Foundation One; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nucana; Honoraria (self), Advisory / Consultancy: Chugai; Research grant / Funding (institution): Aprea; Research grant / Funding (institution): Novartis. U. Banerji: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Karas Therapeutics; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Astex; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Phoenix ACT; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): ONX; Research grant / Funding (institution): BTG; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Verastem. C. Shepherd: Full / Part-time employment: AstraZeneca. W. Brugger: Full / Part-time employment: AstraZeneca. I.A. McNeish: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.
Invited Discussant LBA60 and 993O (ID 6753)
- Domenica Lorusso (Milan, Italy)