Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.

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Combretastatin A-4 phosphate (CA4P) carboplatin and paclitaxel in patients with platinum-resistant ovarian cancer: Final phase II trial results

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5502 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 5502-5502 ◽

Cited By ~ 3

Author(s):

M. Zweifel ◽

G. Jayson ◽

N. Reed ◽

R. Osborne ◽

B. Hassan ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Trial ◽

Randomised Trial ◽

Full Data ◽

Vascular Disrupting Agent ◽

Platinum Resistant ◽

Grade 3 ◽

Start Trial

5502 Background: CA4P is a vascular disrupting agent that in pre-clinical models can increase the efficacy of a variety of therapies. A dose escalation trial of CA4P given prior to carboplatin, paclitaxel or both showed the combination was well tolerated and responses were seen in several tumor types including 6/17 with relapsed ovarian cancer. The trial was therefore extended into a phase II trial in patients with platinum resistant ovarian cancer. Methods: Patients with ovarian cancer that had relapsed and could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63mg/m2 18–20 hours prior to paclitaxel 175mg/m2 and carboplatin AUC 5 repeated 3 weekly. If > 2 responses were seen in first 18 patients 43 patients were to be treated to confirm response rate>19%. Results: Five of the first 18 patients responded so the study was extended and closed after 44 patients were recruited, with full data available to date on 34. Weekly blood counts have demonstrated grade 3/4 neutropenia in 11 and thrombocytopenia in only 1 patient. Other grade > 2 toxicity seen in > 1 patient was fatigue, nausea / vomiting, pain, alopecia, rapidly reversible ataxia, diarrhoea, neuropathy and was little different to what would be expected with paclitaxel and carboplatin. Hypertension is the commonest CA4P related toxicity and was easily controlled by GTN, then prophylactic amlodipine. Responses according to GCIG criteria, have been seen in 11/34 (32%) patients with an additional unconfirmed PR. Conclusions: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will hopefully confirm this. [Table: see text]

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EFFORT: EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5505 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5505-5505

Author(s):

Shannon Neville Westin ◽

Robert L. Coleman ◽

Bryan M. Fellman ◽

Ying Yuan ◽

Anil K. Sood ◽

...

Keyword(s):

Ovarian Cancer ◽

Dose Reduction ◽

Phase Ii ◽

Clinical Benefit ◽

Parp Inhibitor ◽

Objective Response ◽

Cell Cycle Checkpoint ◽

M Cell ◽

Peritoneal Cancer ◽

Grade 3

5505 Background: Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. The Wee1 inhibitor, adavosertib, has demonstrated activity alone and in combination with olaparib in PARP inhibitor (PARPi)-resistant preclinical models. We sought to evaluate efficacy of adavosertib (A) with or without olaparib (O) in a phase II noncomparative study of recurrent PARPi-resistant ovarian cancer. Methods: Women with recurrent ovarian, fallopian tube or primary peritoneal cancer with documented progressive disease on a PARPi were eligible. All patients (pts) had measurable disease and adequate end organ function. On the A arm, pts received A 300mg PO daily on days 1-5 and 8-12 of a 21-day cycle. On the A/O arm, pts received A 150mg PO BID on days 1-3 and 8-10 and O 200mg PO BID on days 1-21 of a 21-day cycle. Primary endpoint was objective response per RECIST 1.1 and was assessed every 2 cycles. Clinical benefit rate (CBR) was defined as proportion of pts with objective response or stable disease > 16 weeks. Progression free survival (PFS) was assessed using the Kaplan Meier method and calculated from date of treatment initiation to earliest date of progression, death, or last visit. Results: 116 pts were screened with 80 pts enrolled and randomized (A: n=39, A/O: n=41). Median age was 60 years (range 36-76) and the majority of pts had platinum resistant disease (64%) and high grade serous histology (98%). Pts received a median of 4 prior therapies (range 1-11) and 48% had germline or somatic BRCA mutations. There were 35 pts evaluable for response in each arm. Table demonstrates efficacy data. On the A arm, Grade 3/4 toxicities occurred in 51% of pts, most commonly neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%). 28 (72%) pts required at least one dose interruption and 20 (51%) required dose reduction. On the A/O arm, Grade 3/4 toxicities occurred in 76% of pts, most commonly thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%), and anemia (10%). 36 (88%) of pts required at least one dose interruption, 29 (71%) required dose reduction, and 4 (10%) did not restart due to toxicity. Conclusions: A given alone and in combination with O demonstrated efficacy in pts with PARPi-resistant ovarian cancer. Although grade 3 and 4 toxicities were observed on both arms, these were generally manageable with supportive care, dose interruptions and dose reductions as needed. Additional translational analyses are ongoing to clarify which pts received clinical benefit. Clinical trial information: NCT03579316. [Table: see text]

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Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study

Journal of Clinical Oncology ◽

10.1200/jco.2015.62.1474 ◽

2016 ◽

Vol 34 (7) ◽

pp. 706-713 ◽

Cited By ~ 35

Author(s):

Eric Pujade-Lauraine ◽

Frédéric Selle ◽

Béatrice Weber ◽

Isabelle-Laure Ray-Coquard ◽

Ignace Vergote ◽

...

Keyword(s):

Quality Of Life ◽

Ovarian Cancer ◽

Disease Control ◽

Phase Ii ◽

Kinase Inhibitor ◽

Single Agent ◽

Progression Free Survival ◽

Platinum Resistant ◽

Grade 3

Purpose Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. Patients and Methods Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator’s choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. Results Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. Conclusion Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.

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Combined regimen of inhalable STING agonist plus chemoimmunotherapy in platinum-resistant or platinum-refratory ovarian cancer: A randomized, open-label, phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6071 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6071-6071

Author(s):

Yan Zhang ◽

Qian Mei ◽

Yuanguang Meng ◽

Meixia Chen ◽

Yang Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Disease Control ◽

Phase Ii ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Objective Response ◽

Advanced Ovarian Cancer ◽

Effective Control ◽

Hematological Toxicity ◽

Platinum Resistant

6071 Background: Approximately 70% patients with advanced ovarian cancer have a relapse and ultimately succumb to their disease. Treatment options are limited in this context with an unacceptable low response (less than 20%). Immunotherapy with checkpoint inhibitors presented to date are not very convincing with 10-15% response because of inadequate immunity. We previously discovered the critical role of manganese in innate immune sensing of tumors by activating STING signaling. This ongoing, randomized, phase II study is to assess STING agonist plus nPP chemotherapy and anti-PD-1 antibody sintilimab in platinum-resistant/refractory ovarian cancer. Methods: Enrolled patients were 2:1 randomizedly assigned to receive nab-paclitaxel (180-220mg/m2), cisplatin (60-80mg/m2) and sintilimab 200mg per 3 weeks with (cohort 1) or without (cohort 2) inhalable MnCl2 (0.4mg/kg) daily. Safety was assessed by CTCAE v5.0, and clinical response by MRI or CT every 2 cycles referred to RECIST version 1.1. The primary endpoints were objective response rate (ORR) and safety. Key secondary end points were disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: 27 patients were enrolled, and 21 were included in efficacy population by the end of Jan. 2020. All enrolled patients were with heavily treated history, median 4 lines of prior therapy, median 19 cycles of multiagent regimens. The addition of MnCl2 to the combined chemo-immunotherapy did not appear to exacerbate treatment-related adverse events (AEs). The most common AEs are hematological toxicity (87%), nausea (56%) and vomiting (47%) in both two cohorts. All 14 evaluable patients (14/19) from cohort 1 had an effective control (11 PR [78.6%], 3 SD [21.4%]) . Ten patients (71.4%) achieved PR at the first tumor scan assessment. For 8 cases from cohort 2, 7 were assessable and all showed SD, 4 of whom exhibited SD with enlarged lesions and disease progression after 4-cycle treatment. Conclusions: MnCl2 administration induced encouraging objective clinical responses (78.6%) and disease control (100%) in relapsed/refractory ovarian cancer. The combined regimen showed accepted and manageable safety profile. Clinical trial information: NCT03989336.

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Phase II study of MKC-1 in patients with metastatic or resistant epithelial ovarian cancer or advanced endometrial cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5577 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 5577-5577 ◽

Cited By ~ 2

Author(s):

C. Elser ◽

H. Hirte ◽

L. Kaizer ◽

H. Mackay ◽

S. Bindra ◽

...

Keyword(s):

Ovarian Cancer ◽

Endometrial Cancer ◽

Phase Ii ◽

Phase Ii Study ◽

Single Agent ◽

Gastrointestinal Disorder ◽

Ca 125 ◽

Platinum Resistant ◽

Parallel Group ◽

Grade 3

5577 Background: MKC-1 is a novel oral cell cycle inhibitor with preclinical activity in xenograft models of human ovarian and endometrial cancers. MKC-1 also reduces pAKT, an attractive target in endometrial cancer due to frequent PTEN mutations. Methods: The objective of this phase II study is to assess the efficacy of MKC-1 in 2 patient (pt) populations: metastatic or recurrent platinum-resistant ovarian cancer (EOC) and advanced endometrial cancer (EC). Three prior lines of treatment were allowed in both groups. A two arm, parallel group multicenter 2-stage design was used. The primary endpoint was tumor response by RECIST or CA-125. MKC-1 125 mg/m2 was administered orally twice daily for 14 days in 28-day cycles. Results: Accrual to stage one is complete with 21 pts in each arm. 19 pts with EOC (median age 56 yrs, range 31–71) and 9 patients with EC (median 63 range 50–74) were available for efficacy. A total of 66 cycles (EOC/EC: 39/27cycles) median 2 per patient (range 1–8) were delivered. 11/4 pts had prior adjuvant CT, 14/10 had prior systemic CT for advanced disease, and 2/6 received prior radiation. In pts with EOC, 7 pts have stable disease (SD), 12 progressive disease (PD), 2 remain on study. Median time to progression is 1.8 months. In pts with EC 4 pts had SD, 5 PD, 6 remain on study. Toxicity data are available in 28 pts (17/11). Most common adverse events (AE) possibly related to MKC-1 were fatigue, nausea, elevated ALT or AST, urine discoloration, anemia, anorexia, elevated AP and gastrointestinal disorder in 55%, 39%, 36%, 24%, 23%, 21%, 21%, and 21 % of cycles respectively. The only possibly related grade 3+ AEs were neutropenia, leucopenia and hyponatremia in 9 %, 3 %, and 2% of cycles. Conclusions: MKC-1 was well tolerated in both patient populations. Single agent MKC-1 has insufficient activity in platinum resistant EOC to warrant further investigation. Updated clinical data for both patient groups will be presented at the meeting. [Table: see text]

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Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK – A16037)

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920975352 ◽

2020 ◽

Vol 12 ◽

pp. 175883592097535

Author(s):

Susana Banerjee ◽

Holly Tovey ◽

Rebecca Bowen ◽

Elizabeth Folkerd ◽

Lucy Kilburn ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Phase Ii ◽

Clinical Benefit ◽

Objective Response ◽

Evaluation Criteria ◽

Clinical Activity ◽

Low Grade ◽

Open Label ◽

Grade 3

Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC. Patients & Methods: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks. Results: A total of 42 patients were recruited; median age 65 (range 34–85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays. Conclusions: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation. Trial registration: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050

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Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: A Randomized Multicenter Phase II Trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.8911 ◽

2011 ◽

Vol 29 (2) ◽

pp. 242-248 ◽

Cited By ~ 64

Author(s):

Jalid Sehouli ◽

Dirk Stengel ◽

Philipp Harter ◽

Christian Kurzeder ◽

Antje Belau ◽

...

Keyword(s):

Ovarian Cancer ◽

Treatment Option ◽

Phase Ii ◽

Clinical Benefit ◽

Phase Ii Trial ◽

Progression Free Survival ◽

Complete Response ◽

Recurrent Ovarian Cancer ◽

German Society ◽

Platinum Resistant

PurposeWeekly administration of topotecan (Tw) is less toxic and widely considered a better treatment option than conventional 5-day therapy (Tc) in women with platinum-resistant recurrent ovarian cancer. We conducted a randomized phase II trial (TOWER [Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer]) to better define the ratio between benefits and risks with either treatment approach.Patients and MethodsPatients were randomly assigned to two independent two-stage protocols of Tw (4 mg/m2/wk administered on days 1, 8, and 15) or Tc (1.25 mg/m2/d on days 1 to 5). We evaluated risk ratios (RRs) for the primary end point of clinical benefit (complete response, partial response, and stable disease), the duration of progression-free survival (PFS) and overall survival (OS), associated hazard ratios (HRs), and RRs of toxicity with 95% CIs.ResultsIn total, 194 patients were randomly assigned at 54 centers to Tw (n = 97) or Tc (n = 97). Clinical benefit was observed in 36 of 76 (47%; 95% CI, 36% to 59%) Tw and 46 of 80 (58%; 95% CI, 46% to 68%) Tc patients (RR, 1.21; 95% CI, 0.90 to 1.64; P = .205). Patients in the Tw group had a slightly shorter PFS (HR, 1.29; 95% CI, 0.96 to 1.76) but similar OS (HR, 1.04; 95% CI, 0.74 to 1.45) compared with Tc. Tw was associated with significantly lower risks of anemia (RR, 0.35; 95% CI, 0.16 to 0.79), neutropenia (RR, 0.38; 95% CI, 0.23 to 0.65), and thrombocytopenia (RR, 0.23; 95% CI, 0.09 to 0.57).ConclusionWith regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.

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Ixazomib, Thalidomide and Dexamethasone (IxaThalDex) in Relapsed/Refractory Multiple Myeloma (RRMM): An Interim Analysis of a Phase II Trial

Blood ◽

10.1182/blood.v128.22.3335.3335 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3335-3335 ◽

Cited By ~ 3

Author(s):

Heinz Ludwig ◽

Eberhard Gunsilius ◽

Michael Fridrik ◽

Richard Greil ◽

Andreas Petzer ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Clinical Benefit ◽

Research Funding ◽

Phase Iii ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Clinical Benefit Rate ◽

Grade 3

Abstract Introduction Ixazomib, a second generation proteasome inhibitor provides the advantage of combining oral administration with pronounced activity and a favorable toxicity profile. Phase II studies employing ixazomib-dexamethasone established a once weekly dosing regimen and showed substantial activity in RRMM yielding response rates of up to 58% when combined with lenalidomide-dexamethasone (Ld). A recent phase III trial proved the superiority of the triple combination ixazomib-Ld compared to Ld in patients with RRMM. Here, we evaluate the activity and tolerability of the all oral combination ixazomib-thalidomide-dexamethasone in patients with RRMM. Methods Patients with RRMM with at least 1 prior line of therapy were enrolled. Patients had to have measurable disease, ECOG performance status ≤2, ANC ≥1000/µL, platelet count ≥50000µL, GFR ≥15mL/min. The treatment regimen consisted of ixazomib (4mg, d 1, 8 and 15), thalidomide (100mg daily) and dexamethasone (40mg once weekly). Patients aged ≥75 years received a reduced dose of both thalidomide (50mg daily) and of dexamethasone (20mg, once weekly). A total of 8 cycles was planned, followed by ixazomib maintenance therapy (4mg, days 1, 8, 15 of a 28 cycle and 3mg in patients aged ≥75 years) for one year. Progression-free survival curves were estimated using the Kaplan-Meier method. The EORTC Q30 instrument was used for evaluation of changes in overall health and global QoL during therapy. Results Thirty-nine of 77 planned patients have been enrolled so far. Intent-to treat group (ITT), age, median: 67, range 42 to 85; ISS stage I: 13, II 14, III: 10, not known: 2, number of prior treatment lines, median: 2, (range: 1-5). Seven patients have discontinued treatment before completion of 2 cycles (early death: 3, progressive disease: 2, protocol violation: 1, patients request: 1). At present, 8 patients are too early (not yet completed 2 cycles) for evaluation per protocol (PP). Full documentation of at least 2 cycles of therapy is available for 24 patients. In this group, the median number of cycles administered is 4, and the median follow up is 4.5 months. Responses to IxaThalDex were seen in 14 patients (35.8% and 58.3% of ITT and PP group, respectively), 3 achieved ≥ VGPR (8%/ITT, 13%/PP), 10 PR (26%/ITT, 42%/PP) and 2 MR (5%/ITT, 8%/PP), yielding a clinical benefit rate of 38.5%/ITT, 62.5%/PP. FISH data are available in 17 of the 24 PP patients. Responses (≥PR) were seen in 5/6 patients with t (4;14) and/or t (14;16) and/or del17p and in 5/8 with standard risk cytogenetics. Median PFS at the time of reporting is 5.7 and 6.4 months in the ITT and PP group, respectively. An improvement in overall health and of general QoL was noted in 6 and 7 of the 14 responders, respectively. Toxicity data are presented for the PP group. Neutropenia was the most common hematologic toxicity noted in 20 (83.3%) patients; all of them had grade 1/2, and none higher grade neutropenia. Leukopenia was seen in 15 (62.5%) patients, (14 grade 1/2 and one grade 3). Sixteen (66.7%) had grade 1/2 anemia. Grade 1/2 thrombocytopenia was noted in 8 (33.3%) patients. The most frequent non hematological toxicity was infection seen in 7 (29%) patients. Six were grade 3; pneumonia was seen in 4, sepsis in 1 and other infections in 2 patients. Polyneuropathy at baseline was seen in 7 patients (grade 1 in 2, and grade 2 without pain in 6 patients). During the study the incidence of new PNP was relatively rare (3 new and one worsening PNP) with presently 9 (37.5%) patients with grade 1-2 and only 1 (4.2%) with grade 3. Other notable toxicities were acute renal failure (grade 3) in 2 (8.3%), fatigue in 8 (4 grade 1, 4 grade 2), constipation and diarrhea (all grade 1) each in 4, and edema and vision impairment (all grade 1), each in 3 patients. Conclusion The entirely oral IxaThalDex regimen resulted in an ORR of 58.3 in the PP and of 35.8% in the ITT population (with 8 patients being too early for PP evaluation and not having reached 2 cycles as yet). The clinical benefit rate was 62.5% and 38.5% for the PP and ITT group, respectively. Median PFS was 6.4 months in the PP group. General health and QoL improved in 42.8% and 50% of the responders. The ixazomib-thalidomide-dexamethasone regimen was well tolerated and with relatively few side effects being noted. As exposure to therapy is still short at this point of time it is anticipated that efficacy data will further improve with longer therapy and follow up. Updated results will be presented at the meeting. Disclosures Ludwig: Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Greil:Celgene: Research Funding; Takeda: Honoraria, Research Funding; Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Petzer:Roche: Honoraria. Knop:Takeda: Consultancy. Poenisch:Mundipharma: Research Funding.

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