Common Related Grade Research Articles

Abstract CT110: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in solid tumor cohorts

Abstract Background: Aberrant splicing contributes to the progression of cancer but lacks targeted drugs. CTX-712 is a potent oral CDC2-like kinase (CLK) inhibitor affecting RNA splicing, CTX-712 demonstrated potent inhibition of proliferation in human tumor cell lines and elicited robust anti-tumor activity in xenograft models. This study aimed to evaluate CTX-712’s maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK)/pharmacodynamics (PD) profiles, and preliminary efficacy in patients with advanced solid tumors. Methods: This study consisted of a dose escalation cohort (A) and three dose expansion cohorts (C, D and E) for solid tumors. The dose escalation cohort (A) was initiated with accelerated titration and then switched to a 3+3 design (10, 20, 40, 70, 105, 140 and 175 mg twice a week [TW]). The dosing regimens for dose expansion cohorts were 105 mg TW (C), 70 mg TW (D), and 105 mg once a week (QW) (E). Results: As of November 20, 2023, a total of 46 patients with solid tumors were enrolled in the dose escalation cohort (16 patients) and dose expansion cohorts (30 patients total). In the dose escalation cohort, CTX-712 was administered at a dose of 10/20/40/70 mg TW (n=1 each), 105/175 mg TW (n=3 each) and 140 mg TW (n=6). DLTs were observed in 2 patients (140 mg TW [platelet count decreased, hypokalemia], 175 mg TW [dehydration]) and MTD was determined to be 140 mg TW. Among the safety analysis population (n=46), median treatment duration was 77 days (Range 1-413+ days); 1 patient is ongoing, and 45 patients discontinued. The common any-grade related adverse events (AEs) (≥30%) were nausea (93.5%), vomiting (65.2%), diarrhea (54.3%), decreased appetite (45.7%) and blood creatinine increase (32.6%). The most common related Grade 3 or higher AE was platelet count decrease (6.5%). Among all the patients (n=46), partial responses were observed in 4 (8.7%) patients (40 (n=1)/70 (n=2)/105 (n=1) mg TW cohorts), who were all patients with ovarian cancer; the median treatment duration of ovarian cancer (n=14) was 84 days (Range 1-413+ days). In PK analysis, a dose-dependent increase in systemic exposure of CTX-712 was observed. PD response was assessed in RNA extracted from peripheral blood cells. Dose-dependent increases of exon skipping in two marker RNAs (S6K and THAP9-AS1) demonstrated mRNA splicing modification induced by CTX-712. Conclusions: CTX-712 demonstrated an acceptable safety profile in patients with solid tumors. Additionally, CTX-712 demonstrated favorable clinical efficacy for patients with ovarian cancer and further investigation is warranted. Clinical trial information: jRCT2080224127 Citation Format: Noboru Yamamoto, Takafumi Koyama, Yuki Katsuya, Jun Sato, Toshio Shimizu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Kan Yonemori. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in solid tumor cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT110.

Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C) and hydroxychloroquine (HCQ) neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).

667 Background: Neoadjuvant therapy has become the consensus treatment for individuals with locally advanced (LA) and borderline resectable (BR) PDAC. Neoadjuvant therapy for resectable (R) PDAC has been in greater use due to concerns over micro metastases at diagnosis. Typical therapies involve the use of multiagent systemic chemotherapy with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. HCQ has been shown to target autophagy in PDAC and has demonstrated higher response in combination with GA. We conducted a prospective, phase 2 clinical trial of patients with R, BR, and LA PDAC utilizing a regimen combining A + G + C + HCQ with the primary endpoint of CA 19-9 normalization (NCT04669197). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1, 8 of a 21-day cycle (IV) along with HCQ 600 mg po bid. Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate (by RECIST 1.1), and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date all planned 12 patients have been enrolled, 11 evaluable. 8 male, 4 female; age range 50 to 76 yo. Patient classifications is 3 R; 4 BR; 5 LAPC. Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 27%, gr 4 27%, anemia gr 3 36%, and neuropath gr 3 36%. CA 19-9 normalization occurred in 36% (4/11) who have completed at least 1 cycle of treatment. To date, 3 individuals went to surgery, with 3 achieving R0. Overall response rate in measurable patients is 45% (1CR, 4 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+HCQ resulted in a CA 19-9 normalization rate in 36% of individuals. Most patients did not go to surgery. The OS data is maturing. Supported by grants from the HonorHealth Foundation and Marley Foundation. Clinical trial information: NCT04669197 .

Panitumumab in combination with chemoradiotherapy for the treatment of locally-advanced anal canal carcinoma: Results of the FFCD 0904 phase II trial

Background and purposeStandard treatment of squamous cell carcinoma of the anus (SCCA)is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study (EudraCT: 2011–005436-26) assessed the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU-based CRT. MethodsPatients with locally advanced tumors without metastases (T2 > 3 cm, T3-T4, or N + whatever T stage) were treated with IMRT up to 65 Gy and concomitant CT according to the doses defined by a previous phase I study (MMC: 10 mg/m2; 5FU: 400 mg/m2; Pmab: 3 mg/kg). The expected CR rate was 80%. ResultsForty-five patients (male: 9, female: 36; median age: 60.1 [41.5–81]) were enrolled in 15 French centers. The most common related grade 3–4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (13.3%), and asthenia (11.1%) with RT interruption in 14 patients. One patient died because of mesenteric ischemia during the CRT, possibly related to treatment. In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4–78.2]. Median follow-up was 43.6 months [IC 95%: 38.61–47.01]. Overall survival, recurrence-free and colostomy-free survival at 3 years were 80% [95%CI: 65.1–89], 62.2% [IC95%: 46.5–74.6] and 68.8 % [IC95%: 53.1–80.2] respectively. ConclusionPanitumumab in combination with CRT for locally advanced SCCA failed to meet the expected CR rate and exhibited a poor tolerance. Furthermore, late RFS, CFS, and OS did not suggest any outcome improvement to justify further clinical trials.ClinicalTrials.gov identifier: NCT01581840.

Abstract CT001: A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial

Abstract Background: Targeting of mutation-derived epitopes (neoantigens) by T cells has been demonstrated to drive anti-tumor immune responses. mRNA-4157 is a novel mRNA-based personalized cancer vaccine, which encodes up to 34 patient-specific tumor neoantigens. It was hypothesized mRNA-4157 could synergize with adjuvant pembrolizumab to improve recurrence free survival (RFS) in patients with resected stages IIIB/IIIC/IIID and IV melanoma. Methods: Eligible patients with completely resected, high-risk cutaneous melanoma were randomly assigned 2:1 (stratified by stage) to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. mRNA-4157 (1mg) was administered intramuscularly every 3 weeks for a total of 9 doses and pembrolizumab (200mg) intravenously was given every 3 weeks for up to 18 cycles. Safety was evaluated as a secondary endpoint. RFS in the overall intention-to-treat population was the primary end point. The study was designed with 80% power to detect a hazard ratio (HR) of 0.5 with an overall 1-sided type I error of 0.1 when a total of 40 RFS events were observed. The primary analysis for RFS was specified to occur after all patients completed a minimum of 12 months on study and at least 40 RFS events were observed. Results: 107 patients received the combination of mRNA-4157 with pembrolizumab and 50 patients were treated with pembrolizumab monotherapy. Recurrence or death was reported in 24 of 107 patients (22.4%) in the combination arm and in 20 of 50 patients (40%) in the monotherapy arm, at a median follow-up of 101 and 105 weeks respectively. 18-month RFS rates (95% CI) were 78.6% (69.0%, 85.6%) vs 62.2% (46.9%, 74.3%) in the combination and monotherapy arm respectively. The combination showed protocol defined statistical significance and a clinically meaningful improvement in RFS compared to pembrolizumab, with a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017); stratified log-rank test 1-sided p-value of 0.0266. The majority of treatment related adverse events were Grade 1/2. The number of patients reporting treatment related Grade ≥ 3 adverse events was generally similar between the arms (25% vs 18%, respectively). The most common mRNA-4157 related Grade 3 event was fatigue. No Grade 4 or Grade 5 events related to mRNA-4157 were reported. No potentiation of immune-mediated adverse events were observed with the addition of mRNA-4157 to pembrolizumab. Conclusions: mRNA-4157 in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma significantly prolonged RFS compared to pembrolizumab without an increase in clinically meaningful adverse events. These results are the first to demonstrate improvement of RFS over adjuvant standard of care PD-1 blockade in resected high-risk melanoma and provide the first randomized evidence that a personalized neoantigen approach is potentially beneficial for cancer patients. A phase 3 study will be initiated in patients with melanoma. Citation Format: Adnan Khattak, Matteo Carlino, Tarek Meniawy, George Ansstas, Theresa Medina, Matthew H. Taylor, Kevin B. Kim, Meredith McKean, Georgina V. Long, Ryan J. Sullivan, Mark Faries, Thuy Tran, Charles Cowey, Andrew Pecora, Jennifer Segar, Victoria Atkinson, Geoffrey T. Gibney, Jason Luke, Sajeve Thomas, Elizabeth Buchbinder, Peijie Hou, Lili Zhu, Tal Zaks, Michelle Brown, Praveen Aanur, Robert S. Meehan, Jeffrey S. Weber. A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT001.

Abstract P4-01-38: A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted a non-randomized, open-label, single-arm, multicenter, phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women. Primary objective was progression free survival, PFS. Secondary objectives: objective response rate, ORR (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate, CBR (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 6/30/2022 data cut-off, 2 pts were still on treatment. This is an updated analysis with median follow-up time of 24 months (range 8-51). Median age was 60 (range 39-82). The median PFS was 19.8 months with 95% CI (8-41) for pts with de-novo MBC and 7 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 77% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for AA pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients (8%) developed thromboembolic events (grades 2, 3, 4) and discontinued treatment. One patient died while on treatment from PD. More than 800 exosome proteins were detected in the samples analyzed so far. Exosomal protein networks in pretreatment samples predicted treatment response with 89% sensitivity and 95% specificity in unsupervised clustering. Data on correlative objectives will be presented in a separate abstract. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who present with de-novo metastatic disease and are intolerant to AI; although this small study indicates a lower PFS. Table 1: Baseline Demographics Citation Format: Oana C. Danciu, Kent Hoskins, Jennifer Weiss, Cristina I. Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Yu Gao, Menggang Yu, Qianqian Zhao, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski. A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-38.

A pilot induction regimen incorporating dinutuximab and sargramostim for the treatment of newly diagnosed high-risk neuroblastoma: A report from the Children's Oncology Group.

10003 Background: The addition of dinutuximab (DIN) in the post-consolidation setting led to improved event-free survival rates for patients with high-risk neuroblastoma. Chemoimmunotherapy including irinotecan, temozolomide, DIN and sargramostim (GM-CSF) in patients with recurrent or refractory neuroblastoma results in robust objective clinical responses. Evaluation of chemoimmunotherapy in the induction setting for patients with newly-diagnosed high-risk neuroblastoma (HR-NBL) warrants investigation. Methods: Children’s Oncology Group (COG) ANBL17P1 is a prospective, single arm, limited institution pilot study to assess the tolerability and feasibility of administering DIN (17.5mg/m2/dose, IV Days 2-5) and GM-CSF (250mcg/m2/dose, subcutaneous Days 6-count recovery) with COG Induction chemotherapy Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma. The primary endpoint of tolerability included the number of toxic deaths and number of patients experiencing predefined unacceptable toxicities during Induction Cycles 3-5. Unacceptable toxicities included: hypotension requiring pressors > 24 hours, respiratory toxicity requiring ventilatory support > 24 hours, Grade 4 neuropathy that did not resolve prior to the next cycle, and failure to recover the ANC to > 750 mm3 by day 35. Feasibility was assessed as being able to receive > 75% of planned DIN doses administered during Induction Cycles 3-5. Revised International Neuroblastoma Response Criteria (INRC) were used to assess end of Induction (EOI) response. Results: Forty-two eligible and evaluable patients with newly-diagnosed high-risk neuroblastoma enrolled at 8 sites (22 [52.4%] males; median age 3.3 years at diagnosis) from January 14, 2019 to June 4, 2020. The most common DIN related Grade >3 toxicities observed during Induction Cycles 3-5 included fever (31.0%) and pain (9.5%). None of the patients experienced a toxic death or unacceptable toxicity during Induction Cycles 3-5. Thus, the regimen was deemed tolerable. Patients received 97.4% - 101.8% of the total DIN dose expected to be administered during Induction Cycles 3-5. Therefore, the regimen was deemed feasible. Thirty-eight of 42 patients completed the EOI evaluations, including 11 with complete response, 22 with partial response, 0 with minor response, 3 with stable disease and 2 with progressive disease. The overall EOI objective response rate (CR+PR+MR) was 86.8%. Conclusions: The administration of DIN and GM-CSF to COG Induction Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma was tolerable and feasible. The objective response rate at EOI appears encouraging. This therapeutic regimen will be studied in a randomized phase 3 trial to further evaluate the efficacy of Induction phase chemoimmunotherapy for high-risk neuroblastoma. Clinical trial information: NCT03786783.

A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

A single-arm phase II trial of palbociclib in combination with tamoxifen as first-line therapy for metastatic hormone receptor-positive breast cancer.

1056 Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted an open-label, single-arm, multicenter phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women, but not required. Primary objective was progression free survival. Secondary objectives: objective response rate (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 1/5/21 data cut-off, 7 pts were still on treatment. Median follow-up time was 24 months (range 8-42). Median age was 60 (range 39-82). The median PFS was 14.6 months with 95% CI (7-41) for pts with de-novo MBC and 6 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 78% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for African American pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients developed thromboembolic events (1 grade 2, 2 grade 3, 1 grade 4). One patient died while on treatment from PD. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who are intolerant to AI, although this small study indicates a lower PFS. Clinical trial information: 02668666 .[Table: see text]

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01)

Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

A phase I dose-escalation and pharmacokinetic study of a micellar nanoparticle with entrapped docetaxel (CPC634) in patients with advanced solid tumours

Background: CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies, CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. This phase I dose escalation study is the first-in-human study with CPC634.Methods: adult patients with advanced solid tumours received CPC634 intravenously either 3-weekly (Q3W) (part 1, dose range 15–100 mg/m2), 2-weekly (Q2W) (part 2, 45 mg/m2) or Q3W with dexamethasone premedication (part 3, 60 mg/m2).Results: thirty-three patients were enrolled. Skin toxicity was dose limiting (DLT) at ≥60 mg/m2 in part 1 and at 45 mg/m2 in part 2 and was the most common CPC634 related grade ≥ 3 adverse event (24%). With dexamethasone premedication no DLTs were observed at 60 mg/m2 Q3W. CPC634 exhibited a dose-proportional pharmacokinetic profile. At 60 mg/m2, the plasma area under the curve was 4067.5 ± 2974.0 ng/h/mL and the peak plasma level 217.3 ± 91.9 ng/mL with a half-life of 39.7 ± 9.4 h for released docetaxel.Conclusion: CPC634 could be administered safely upon pretreatment with dexamethasone. Cumulative skin toxicity was the main DLT. The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication.

Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C), and paricalcitol (P)neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).

4631 Background: Localized PDAC management has recently evolved. Due to concerns over micro metastases at diagnosis the use of neoadjuvant chemotherapy for PDAC has become more common. Typical therapies involve the use of multiagent systemic chemotherapies with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. We conducted a prospective, phase 2 clinical trial of patients with resectable (R), BR, and LA PDAC utilizing a regimen combining A + G + C + paricalcitol (P) with the primary endpoint of CA 19-9 normalization (NCT03138720). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2, P at a fixed dose of 25 µg on days 1, 8 of a 21-day cycle (all treatment IV). Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate, and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date 24 of the planned 24 patients have been enrolled. 13 male, 11 female; age range 49 to 84 yo. Patient classifications is 8 R; 7 BR; 9 LAPC. Median baseline CA 19-9 156 (range 45-3674). Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 29%, gr 4 25%, anemia gr 3 45.8%, gr 4 4.2%, and hypophosphatemia gr 3 8.3%. CA 19-9 normalization occurred in 50% (12/24) who have completed at least 1 cycle of treatment. To date, 14 individuals went to surgery, with 13/14 achieving R0, (1 pCR). Overall response rate in measurable patients is 38% (1 CR, 8 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+P resulted in a CA 19-9 normalization rate in 50% of individuals. The study is ongoing and OS data is maturing. Clinical trial information: NCT03138720 .

Abstract P1-19-30: Safety results from a phase 2 study of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Palbociclib is a reversible, oral, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). Palbociclib combined with various endocrine agents showed significantly improved progression-free survival in patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). Preclinical data demonstrates synergy for the combination of tamoxifen and palbociclib and that the combination is effective in a model of acquired tamoxifen resistance. Tamoxifen is an effective treatment for HR+ MBC and presents a different toxicity profile when compared with aromatase inhibitors and fulvestrant. Combining palbociclib with tamoxifen in first line treatment of HR+ MBC offers an alternative to other endocrine combinations. Methods: This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in patients with HR+/HER2-negative advanced BC. The primary objective is to determine the objective response rate (complete or partial response) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease). Secondary objectives are: safety and tolerability, progression-free survival, clinical benefit rate, 2-year overall survival. Correlative objectives will explore alterations in circulating tumor DNA and changes in gene expression pattern at the time of progression. Safety assessments were performed at baseline, days 1 and 15 (first 2 cycles) and day 1 with each subsequent cycles. Adverse events (AEs) were graded according to NCI-CTCAE v4. Results: Forty-nine patients from 6 academic centers were enrolled in this trial at the time of this report. Baseline demographics and disease characteristics are reported in the table. Median age was 60 (range 39-82). Twenty-three (47%) patients presented with de-novo metastatic disease. Out of 26 (53%) patients who presented with recurrent metastatic disease, 13 (50%) were receiving adjuvant treatment with aromatase inhibitors at the time of recurrence and 13 (50%) were on surveillance with no active treatment. The most common drug related grade ≥ 3 AE was neutropenia (46%) that was transient and manageable by dose modifications, with no development of febrile neutropenia. The most common drug-related any grade AEs were neutropenia (68%), fatigue (43%), nausea (41%), anemia (32%), minor infections (30%), thrombocytopenia (29%), hot flashes (27%), lymphocytopenia (16%), alopecia (11%), diarrhea (11%).Two patients developed thromboembolic events (grades 2 and 4) and discontinued treatment. One patient died while on treatment. Conclusions: The combination of palbociclib and tamoxifen was well tolerated with expected toxicities. Neutropenia was the most frequently reported AE. This is one of the first trials to assess safety of the combination of palbociclib with tamoxifen in HR+ MBC and has implications for the early stage setting. Baseline Demographics and Disease CharacteristicsParameterN%SexFemale49100RaceWhite3367Black or African American1123Asian12American Indian or Alaska Native12Unknown36EthnicityHispanic or Latino36Non-Hispanic4694ECOG Performance status0336711531212Menopausal statusPost-menopausal4082Pre-menopausal918Site of metastasesBone3878Liver1326Lung816Other2245Bone only510 Citation Format: Oana C Danciu, Kent Hoskins, Cristina Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Li Liu, Menggang Yu, Deborah Toppmeyer, Ruth O'Regan, Kari Wisinski. Safety results from a phase 2 study of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-30.

A phase II trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs).

619 Background: Neuroendocrine tumors (NETs) are relatively rare and heterogeneous tumors arising throughout the aerodigestive tract, which are incurable and life-limiting when metastatic. Prior studies of checkpoint inhibitors in NET patients have yielded minimal evidence of efficacy. Historically, effective therapies for advanced, progressive NET yield response rates less than 10% and progression-free survival (PFS) durations of approximately 11 months, as compared to approximately 4.5 months with placebo. Methods: We undertook a phase II basket study of atezolizumab in combination with bevacizumab in patients with rare cancers, and present here the data from the pancreatic NET (pNET) cohort and extrapancreatic NET (epNET) cohort, each of which included 20 patients with grade 1-2 NET that was progressive under any prior therapy. Patients received 1200mg of atezolizumab and 15mg/kg of bevacizumab IV q 21 days. The primary endpoint was confirmed objective response by RECIST 1.1. Results: The confirmed objective response rate with this combination was 20% (95% CI 6-44%) in the pNET cohort and 15% (95% CI 3-38%) in the epNET cohort. The median PFS in the pNET cohort is 19.6 months (95% CI 10.6-NR), while it was 14.9 months (95% CI 6.1-NR) in the epNET cohort, 1-year PFS was 75% and 52%, respectively. The combination was well-tolerated in this patient population, with the most common related treatment-emergent adverse events being hypertension (47.5%), proteinuria (37.5%), and fatigue (35%). The most common related grade 3/4 adverse events were hypertension (20%) and proteinuria (7.5%). Conclusions: The combination of atezolizumab and bevacizumab demonstrated moderate clinical activity in patients with advanced NETs. As pre-treatment and on-treatment biopsies were obtained for all patients, correlations with immune infiltration, mutations, and transcriptome alterations should provide additional insight into the mechanisms of response and resistance. Clinical trial information: NCT03074513.

Definitive chemoradiotherapy plus cetuximab for cancer in the oesophagus or gastro-oesophageal junction

BackgroundChemoradiotherapy is standard treatment for localized oesophageal cancer unsuitable for surgery. We aimed to evaluate the efficacy of cetuximab in combination with chemoradiotherapy. MethodsThis non-randomised multicentre phase II trial recruited patients aged 18-75 with WHO performance status 0-2 having squamous cell carcinoma or adenocarcinoma in the oesophagus or gastro-oesophageal junction, T2-4, N0-3, M0 not suitable for surgery. Chemotherapy was three 21-day cycles of fluorouracil 750 mg/m2 D1-5 and oxaliplatin D1 (cycle 1:130mg/m 2, cycle 2-3:85 mg/m 2). Radiotherapy was 50Gy in 2Gy/fraction, 5 days a week, concurrent with cycle 2 and 3 and weekly cetuximab. The primary objective was loco-regional control at one year. Results52 patients were included. 51 were eligible for toxicity and survival analysis and 46 for recurrence analysis. Full radiotherapy dose was delivered to 80%, 75% received all three cycles of chemotherapy and 75% received four or more doses of cetuximab. The most common related grade III-IV adverse events were gastro-intestinal(16), hypersensitivity(6) and infection(5). There were two drug-related deaths. Within six months from the end of treatment, six patients died from complications from fistulas. The loco-regional control rate at one year was 47.3%(95%CI 30.9%-62.1%). Overall survival at three years was 29.1%(95% CI 17.4-41.9%). ConclusionsOxaliplatin and fluorouracil given concurrent with radiotherapy and cetuximab had an acceptable safety profile and showed a clinical response in patients with locoregionally advanced oesophageal cancer unsuitable for surgery. However, the primary end-point was not met, and the addition of cetuximab to definitive chemoradiotherapy cannot be recommended

Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

1032P - Phase I study of low dose whole abdominal radiation therapy (LDWART) in combination with weekly paclitaxel (wP) for platinum resistant ovarian cancer (PROC)

BackgroundHyper-radiation sensitivity is enhanced in cells with mutant p53, which is ubiquitous in high grade serous ovarian cancer (HGSOC). Preclinical data suggests LDWART is a “chemosensitizer” and enhances paclitaxel cytotoxicity. We evaluated the safety and activity of LDWART concurrent with wP (LDWART+wP) in PROC. MethodsPatients (pts) with PROC (progressive disease (PD) < 6 mth from last platinum therapy) were enrolled in a 3+3 dose de-escalation (part A) design, combining wP concurrent with fixed dose LDWART in 60 cGy fractions (twice daily on D1-2 of each week of wP), for 6 continuous weeks. Planned dose levels of wP were 80mg/m2, 70mg/m2, 60mg/m2. After 6 weeks of LDWART+wP, pts received wP chemotherapy alone until PD. Dose expansion (part B) with up to 10 HGSOC pts at maximum tolerated dose (MTD) of LDWART+wP, proceeded to confirm toxicity and activity. ResultsAs of 30/4/2019, 10 pts were enrolled (3 part A, 7 part B). All part B pts had HGSOC. Median lines of prior therapy was 5 (range 1-8), including prior wP in 70%, and prior bevacizumab (bev) in 50% of pts. There was no dose-limiting toxicity (DLT) at wP 80mg/m2 (DLT period = 1st 3 weeks of LDWART+wP), which was deemed the MTD. 6/10 pts completed 6 weeks of LDWART+wP. Discontinuations were due to PD (3/10) or pt withdrawal (1/10). Common related all-grade adverse events (AEs) were nausea (60%), neutropenia (60%), fatigue (60%), neuropathy (40%), diarrhea (30%); common related grade ≥3 AEs were neutropenia (50%) and anemia (20%). Median progression free survival was 3.2 mth and overall survival was 13.5 mth. 9 pts were evaluable for response. 44.4% (4/9) of pts achieved biochemical response, defined as CA125 decrease >50% from baseline, 2/4 were confirmed. 1pt had partial response (PR) despite PD on prior wP, and 5 pts had stable disease (SD), giving an overall response rate of 11.1% (1/9) and disease control rate (PR + SD>6 weeks) of 66.7% (6/9). 3 pts had durable disease control, and completed 12, 18 and 21 weeks of wP respectively. ConclusionsLDWART+wP (80mg/m2) for 6 weeks was safe and tolerable. Encouraging efficacy was seen in this heavily pre-treated population and LDWART+wP may be useful in the context of PROC where bev is contraindicated. Clinical trial identificationNCT02545010. Legal entity responsible for the studyThe authors. FundingRIE2015 National Medical Research Council, National University Cancer Institute Singapore (NCIS) Centre Grant – NCIS Seed Funding. DisclosureD.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. All other authors have declared no conflicts of interest.

Anti-epidermal growth factor receptor therapy in combination with chemoradiotherapy for the treatment of locally advanced anal canal carcinoma: Results of a phase II study with panitumumab (FFCD 0904).

3570 Background: Standard treatment of anal squamous cell carcinoma is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study studied the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU based CRT. Methods: Patients with locally advanced tumor without metastases (Stage T2, T3 or T4, whatever N stage; Stage N1-N3 whatever T stage) were treated with two RT periods (45Gy in 5 weeks and a boost of 20Gy in 2 weeks) with concomitant CT sessions of 5FU/MMC at RT weeks 1 and 5. Pmab was administered on RT weeks 1, 3, 5 and 7 according to the doses defined by a previous phase 1.study (MMC: 10 mg/m² at J1 and J29; 5FU: 400 mg/m² from J1 to J4 and from J29 to J32, Pmab: 3mg/kg). The expected rate of CR at 8 weeks to continue in phase III was 80%. Results: Forty-five patients (male: 9 (20%), female: 36 (80%); median age: 60.1 [41.5-81]) were enrolled in 15 French centers. All patients but one completed the CRT. Median duration of CRT was 52 days [30-76].Fourteen patients had a RT interruption because of toxicity. Most common related grade 3-4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (28.8%) and asthenia (11.1%). On patient died because of mesenteric ischemia during the CRT (total dose: 36 Gy). In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4-78.2]. Median follow-up was 16.2 months [14.1-18.2]. Overall survival, recurrence-free and colostomy-free survival at one year were 94.6% [95%CI: 75.8-98.7], 72.2% [95%CI: 55.0-83.7] and 78.2% [95%CI: 60.6 – 88.6] respectively. Six (13%) patients had a colostomy with abdomino-perineal amputation due to a tumour recurrence. Conclusions: Despite an acceptable tolerance, panitumumab in combination with CRT for locally advanced anal cancer failed to meet the expected CR rate to justify further clinical trials. Clinical trial information: NCT01581840.

Abstract P1-09-11: A phase Ib study of oral administration of lucitanib in combination with fulvestrant in patients with HR+ metastatic breast cancer (mBC)

Abstract FGFR1 amplification could mediate resistance to endocrine therapy and FGFR1 inhibition reverses this resistance. This phase Ib seeks to evaluate whether the combination of lucitanib, a potent FGFR/VEGFR/PDFGR inhibitor, in combination with fulvestrant, an endocrine agent, reverses resistance to fulvestrant. Eligible patients for this study were postmenopausal with ER+/HER2- mBC and have relapsed during or after treatment with fulvestrant. There were 2 parts in the study: a dose allocation to assess the tolerability of the combination in terms of DLTs and MTD using a modified Continual Reassessment Method (mCRM) [part I] and a dose expansion, with patients assigned to 2 different cohorts based on FGFR amplification, to further evaluate the tolerability of the combination and to identify the recommended phase II dose (RP2D) [part II]. Surrogate target hitting biomarkers were also dosed at baseline and on-treatment. The sponsor decided to halt the clinical development in mBC indication and the study was prematurely terminated after 18 patients (15 in part I and 3 in part II). The presentation will focus on these 18 patients. Patients had ECOG PS 0 or 1 and median number of previous treatments in metastatic setting was 3. Two doses of lucitanib (10mg daily n=9 and 12.5mg daily n=6) in combination with 500 mg/month of fulvestrant were tested in part I. At the 10mg dose level, one patient experienced a DLT (grade 3 hypertension). Based on global lucitanib development program data, it was decided to start Part II with lucitanib 10mg daily. The most common related grade ≥3 toxicities occurring in more than 10% of patients were hypertension (78%) and asthenia (22%). All patients required at least one dose interruption mainly for toxicities, while 13 patients (72%) required at least a dose reduction for toxicities. Thirteen patients (72%) withdrew from the study for disease progression, 3 (17%) for adverse events (at 10mg) and 2 (11%) for non-medical reasons. Three patients achieved a confirmed partial response (as per RECIST v1.1), one at 10mg and two at 12.5mg. About 55% of the patients experienced clinical benefit with a median duration of the benefit of 39.6 weeks and a maximun duration of the benefit of 79.1 weeks for 1 patient (PR at Cycle 4). Biomarker modulations were consistent with lucitanib mode of action; targeting VEGFRs (significant increase of VEGFA, IL8, PlGF) and FGFR1 (significant increase of FGF23). The combination is feasible but requires close patient monitoring and intensive management of adverse events. Those are in line with the anti-angiogenic activity of lucitanib. 10mg (N=12)12.5mg (N=6)All (N=18)Objective Response Rate (ORR)n(%) 11 (8.3)2 (33.3)3 (16.7) 95% CI 3[1.5;35.4][9.7;70.0][5.8;39.2]Clinical Benefit Rate (CBR)n(%) 24 (33.3)6 (100.0)10 (55.6) 95% CI 3[13.8;61.0][61.0;100.0][33.7;75.4]Duration of Clinical Benefitmedian (weeks)28.171.339.6 95% CI 3[27.9; 32.7][29.1; 79.1][27.9; 79.1]1: CR or PR 2: CR or PR or stabilization (SD or NonCR/NonPD) &amp;gt;24 weeks or at end of cycle 6 3: 95% Wilson method of Confidence interval of the estimate Citation Format: Campone M, Bachelot T, Penault-Llorca F, Pallis A, Agrapart V, Pierrat M-J, Poirot C, Paux G, Dubois F, Xuereb L, Robert R, Andre F. A phase Ib study of oral administration of lucitanib in combination with fulvestrant in patients with HR+ metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-11.

Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]

A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer.

341 Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stage IV pancreatic cancer. Methods: Eligibility criteria included Stage IV adenocarcinoma of the pancreas, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Doses are nab-paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. The maximum tolerated dose and phase II dose of cisplatin is 25 mg/m2. Results: 25 pts were treated; 24 were evaluable (baseline and ≥ 1 follow up CT scan). The most common drug related grade (gr) 3 - 4 adverse events (AEs), n = 25, were thrombocytopenia 76% (gr 3 = 36%, gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt (gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1). Median time on therapy was 5.5 months, range (1 – 9.5). By RECIST 1.1 criteria, 2 pts had complete response (8.3%), 15 partial response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median overall survival to date as of 11/10/16 is 16.5 months. Conclusions: Although a small study, the high response rate and landmark evolving median survival are very encouraging. This regimen is being expanded in patients with stage IV pancreatic cancer, neoadjuvant and adjuvant settings. Clinical trial information: NCT01893801.