Phase II study of ruxolitinib in patients with pStat3+ breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS1134-TPS1134 ◽  
Author(s):  
Nancy U. Lin ◽  
Rebecca Sue Gelman ◽  
Jane E. Brock ◽  
Aditya Bardia ◽  
Erica L. Mayer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Tissue ◽  
Type I Error ◽  
Objective Response ◽  
Type I ◽  
Metastatic Progression ◽  
Open Label ◽  
Tumor Biopsy ◽  
T Score ◽  
Patient Reported

TPS1134 Background: Multiple lines of evidence implicate the IL-6/JAK2/Stat3 signaling pathway in metastatic progression and therapeutic resistance in breast cancer (Marotta et al, JCI2011; Britschgi et al, Cancer Cell 2012). Ruxolitinib, an oral inhibitor of JAK1 and JAK2, is approved for the treatment of intermediate or high-risk myelofibrosis, but has not been extensively tested in solid tumors. Methods: Pts with triple-negative breast cancer or inflammatory breast cancer of any subtype are eligible for prescreening of archival tumor tissue for pStat3 expression by immunohistochemistry. Pts with high (Cohort A; T-score >5) or low (Cohort B; T-score 3-4) pStat3 expression, measurable disease, adequate organ function, ECOG PS 0-2, and progression through > 1 line of prior therapy may proceed to receive ruxolitinib, 25 mg orally twice daily. Staging studies are performed at baseline (BL) and every 8 weeks (wk). Baseline tumor biopsy is required for pts who have accessible disease, with an optional biopsy at progression. Blood for IL-6, CRP, and circulating tumor cells are collected at BL, Wk 4, and off-treatment. Patient reported outcomes including EORTC QLQ C-30 and the M.D. Anderson Symptom Inventory are collected at BL, Wk 4, Wk 8, and off-treatment. Statistical Considerations: The primary endpoint of this open-label phase 2 trial is objective response by RECIST 1.1. The study is designed to distinguish between a response rate of 5% versus 20% in each cohort, separately. If > 2 responses out of 21 pts are observed in the first stage of Cohort A, a further 20 pts will be entered on that cohort; the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Cohort B will open to accrual if Cohort A passes the first stage. If > 2 responses out of 21 pts are observed in the first stage of Cohort B, a further 20 patients will be entered into Cohort B, and the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Study Status: A total of 85 patients have consented for prescreening of tumor tissue. As of January 3, 2013, 5 of a planned 41 patients with high pStat3 IHC scores have been treated with ruxolitinib, and accrual is ongoing. Clinical trial information: NCT01562873.

scholarly journals OS4.1 MEVITEM: A European, randomized, open-label, Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog (SHH) pathway

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii10-iii10
Author(s):  
D Frappaz ◽  
M Barritault ◽  
L Montané ◽  
F Laigle-Donadey ◽  
O Chinot ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Rate ◽  
Type I ◽  
Filamin A ◽  
Open Label ◽  
Shh Pathway ◽  
Open Label Phase

Abstract BACKGROUND Vismodegib (V) suppresses sonic hedgehog (SHH) signaling. We postulated that vismodegib together with chemotherapy may be more efficient than chemotherapy alone in patients (pts) relapsing of a SHH-activated medulloblastoma (MB). MATERIAL AND METHODS Adult pts with recurrent SHH-MB not previously exposed to temozolomide (T) were randomly assigned (2:1 ratio) to Arm A (V daily 150mg/d, po) + T (D1-5: 150 mg/m2 for cycle 1 and 200 mg/m2 thereafter; n=up to 25pts) or Am B (T alone; n=up to 13pts). Identification of SHH activation was performed centrally by IHC (GAB1, β-catenin, filamin A, and YAP1). NGS analyses were performed to identify the mutations responsible for SHH activation. Primary objectives were to assess the incidence of severe toxicities (safety run-in based on a 3 + 3 design) and the 6-month non-progression rate (NPR-6m) according to WHO criteria and based on central read tumor assessment (Phase II). A Minimax Simon’s two-stage design was used to detect NPR-6m of 55% (p0: 30%, type I error rate of 5%, power of 80%). At first stage, ≥ 3/9 pts without progression at 6m were required for the accrual of 16 additional pts in Arm A. A 3rd independent and parallel arm with V as single agent (Arm C, n= up to15pts) was added for pts previously treated by T. RESULTS 24 SHH-MB pts were enrolled (Arm A: 10, Arm B: 5 and Arm C: 9; median age: 37 y [21–55]). At the end of the safety run-in; no major safety concerns were reported. At the end of Stage I: no objective response were reported and 2 pts among 10 were free of progression at 6m among in Arm A. According to statistical rules, the study was definitively closed to enrolment. NGS analyses showed a PTCH1 inactivating mutation in 6 pts (n=4 in arm A; n= 2 in arm B); a SMO activating mutation in 4 pts (n= 3 in Arm A; n=1 in Arm B). For 1 pt in each arm, no tumor sample was available for analysis, for 1 pt in Arm A DNA quality was insufficient, and for 1 patient in each arm no mutations of SMO, PTCH1, SUFU or SHH were found. Out of the 4 pts in Arm A with an inactivating PTCH1 mutation, only 1 was progression free at 6m. PFS and OS data will be presented at the meeting. CONCLUSION The combination of vismodegib with monthly T failed to demonstrate superior activity as compared with T alone. Further studies are warranted to refine therapeutic indication for vismodegib

Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1002-1002 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Phase Iii ◽  
Open Label ◽  
Cns Disease ◽  
Patient Reported

1002 Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m2 bid po) or L (1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.

Phase II, noncomparative, open label, multicenter, study of osimertinib, in patients with locally advanced or metastatic EGFR mutated, T790M undetectable or unknown non-small cell lung cancer (Stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21116-e21116
Author(s):  
Hector J. Soto Parra ◽  
Laura Noto ◽  
Francesco Verderame ◽  
Domenico Galetta ◽  
Vito Barbieri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Null Hypothesis ◽  
Type I Error ◽  
Objective Response ◽  
Locally Advanced ◽  
Local Therapy ◽  
Attrition Rate ◽  
Type I ◽  
Open Label ◽  
Egfr Tki

e21116 Background: Osimertinib (OSI) is a potent irreversible EGFR TKI approved for 1st line therapy advanced EGFR+ NSCLC and for 2nd line T790M+ pts. The AURA trial showed promising results even in pts with T790M- NSCLC after no immediate prior OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI and subsequent chemotherapy. Methods: This phase II trial was performed to investigate the role OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI (1 or 2 generation) and subsequent chemotherapy. Eligible pts (M or F, > 18 years, ECOG 0-2) received OSI (80 mg/day) until disease progression or unacceptable toxicity. Objective response rate (ORR) was the primary endopoint. Assuming a 10% attrition rate, 90 pts were planned to be enrolled according to the Optimal Simon’s 2 stage design. In the first stage, 32 pts were planned to be accrued, and if ≤ 3 responses were observed the study would be stopped. Otherwise, 49 additional pts were planned to be accrued. The null hypothesis would have been rejected if ≥ 12 responses were observed. This design yields a type I error rate of 0.05 and 80% power. Results: From May 2017 to October 2020, a total of 54 pts were enrolled (17 M and 37 F, mean age 66 years). The study was stopped early due to an extremely slow enrolment rate. However, the ORR of 31.5% (95% CI 19.5% - 45.5%) was significantly higher than the null hypothesis of 9% (p<0.0001). 17 pts obtained a partial response and 20 a stable disease with an overall disease control rate of 68.5%. Median PFS was 9 mos and median OS was 15 mos. Forty-one pts experienced at least 1 adverse event (51.8% treatment related), more than 90% Grade 1 or 2, the most common being diarrhea. Conclusions: Despite early termination and incomplete recruitment, the treatment with OSI in pts with undetectable or unknown T790M showed a significant ORR and a PFS in line with results in T790M+. Currently, OSI represents the preferred option in naïve pts with EGFR+ NSCLC, regardless of T790M status and for pts who progress the recommended subsequent therapies include local therapy, continuing OSI or chemotherapy; in this new scenario, our results confirm that OSI rechallenge in subsequent line after chemotherapy should be explored. This research was conducted with support from AstraZeneca. Clinical trial information: 2016-002555-17.

Randomized phase II trial of venetoclax + fulvestrant versus fulvestrant in estrogen receptor+, HER2– locally advanced or metastatic breast cancer following recurrence or progression during or after a CDK4/6 inhibitor: VERONICA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS1108-TPS1108
Author(s):  
Geoffrey J Lindeman ◽  
Aditya Bardia ◽  
Rebecca Bowen ◽  
Aulde Flechais ◽  
Guiyuan Lei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Ecog Performance Status ◽  
Patient Reported

TPS1108 Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.

scholarly journals A platform trial in practice: adding a new experimental research arm to the ongoing confirmatory FLAIR trial in chronic lymphocytic leukaemia

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Dena R. Howard ◽  
Anna Hockaday ◽  
Julia M. Brown ◽  
Walter M. Gregory ◽  
Susan Todd ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Type I Error ◽  
Lymphocytic Leukaemia ◽  
Experimental Therapy ◽  
Type I ◽  
Open Label ◽  
Additional Funding ◽  
Trial Structure ◽  
Randomised Controlled ◽  
The Uk

Abstract Background The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success. Methods FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial. Results The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres. Conclusions FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community. Trial registration ISRCTN Registry ISRCTN01844152. Registered on August 08, 2014

A phase 2 study of pamiparib in the treatment of patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1087-1087
Author(s):  
Tao Sun ◽  
Yanxia Shi ◽  
Jiuwei Cui ◽  
Yongmei Yin ◽  
Quchang Ouyang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Objective Response ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Her2 Breast Cancer

1087 Background: Breast cancer is the most common cancer among women, with up to 37% of patients (pts) harboring germline BRCA1/2 mutations (g BRCA1/2m) that appear to be sensitive to poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) inhibition. Pamiparib is an orally administered selective PARP1/2 inhibitor that has the potential to cross the blood-brain barrier. This study evaluated the efficacy and safety of pamiparib in pts with locally advanced/metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious g BRCA1/2m, who received ≤ 2 prior lines of chemotherapy. Methods: In this open-label, phase 2, multi-center study in China (NCT03575065), pts with locally advanced/metastatic HER2- breast cancer with deleterious or suspected deleterious g BRCA1/2m triple negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+ cohort) were enrolled. Pts received pamiparib 60 mg orally twice daily in 28-day cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR) and progression free survival (PFS) by IRC, overall survival (OS), safety and tolerability. Results: 88 pts were enrolled (median age 45.5 years), 76 pts (TNBC cohort n = 55; HR+ cohort n = 21) had measurable disease at baseline per IRC. 60 pts (68.2%) received 1 or 2 prior lines of chemotherapy; 42 pts (47.7%) were treated with platinum previously. Median follow-up was 13.77 months (TNBC cohort, 10.87 months; HR+ cohort, 18.45 months). In the TNBC cohort: confirmed ORR was 38.2% (95% CI: 25.4–52.3); median DOR (mDOR) was 6.97 months (95% CI: 3.94–not estimable[NE]); median PFS (mPFS) was 5.49 months (95% CI: 3.65–7.33); median OS (mOS) was 17.08 months (95% CI:13.70–NE). In the HR+ cohort: confirmed ORR was 61.9% (95% CI: 38.4–81.9); mDOR was 7.49 months (95% CI: 5.55–14.75); mPFS was 9.20 months (95% CI: 7.39–11.93); mOS was not reached (NR; 95% CI 18.10–NE). ≥ Grade 3 treatment emergent adverse events (TEAEs) occurred in 54 pts (61.4%); anemia was the most common TEAE, occurring in 77 pts (87.5%). Dose reduction due to TEAEs occurred for 57 pts (64.8%); discontinuations due to TEAEs occurred for 2 pts (2.3%). Conclusions: Pamiparib showed a promising response in pts with locally advanced/metastatic HER2- breast cancer with a g BRCA1/2m. The safety profile of pamiparib was considered acceptable and was generally consistent with therapies in the same class. Clinical trial information: NCT03575065 .[Table: see text]

Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: Results of Part B (pembrolizumab + chemotherapy).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4148-4148
Author(s):  
Jennifer A. Chan ◽  
Nitya Prabhakar Raj ◽  
Rahul Raj Aggarwal ◽  
Susan Calabrese ◽  
April DeMore ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Large Cell ◽  
Small Cell ◽  
Type I ◽  
First Line ◽  
Open Label ◽  
Total N ◽  
Poorly Differentiated ◽  
Neuroendocrine Carcinomas

4148 Background: The efficacy of immune checkpoint inhibitor (CPI) therapy has not been established in extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). In small cell lung cancer, CPI therapy is approved for use in the first-line and salvage settings. We investigated the efficacy and safety of pembrolizumab (PEM)-based therapy in biomarker-unselected patients (pts) with EP-PDNECs. PEM alone (Part A, N=14) was inactive (ASCO GI 2019; Abstr#363). We now report the results of Part B (PEM plus chemotherapy). Methods: We conducted an open label, multicenter, phase 2 study of PEM-based therapy in pts with EP-PDNECs, excluding Merkel cell carcinoma and well differentiated grade 3 neuroendocrine tumors (NET), with disease progression on first-line systemic therapy. In Part B of this trial, patients were treated with PEM 200 mg IV every 3 week cycle plus dealers’ choice chemotherapy (chemo): weekly irinotecan (IRI, 125 mg/m2 day 1,8 of every 21 day cycle) or weekly paclitaxel (PAC, 80 mg/m2). After PEM/IRI safety lead-in (N=6), 16 additional pts (total N=22) were enrolled. This was based on a primary endpoint of objective response rate (ORR) by RECIST 1.1 and a plan to test Ha ORR 31% vs H0 ORR 10% with 80% power at a type I error rate of 0.05. Secondary endpoints include safety, overall survival (OS), and progression-free survival (PFS). Serial blood samples and baseline tumor biopsies were required in all pts. Results: Preliminary data from Part B are available. Of 22 pts enrolled, male/female 15/7; median age 57 years (range 34-75); ECOG PS 0/1: 10/12; 6 large cell, 8 small cell, 8 NOS. Primary sites of disease: GI 73%, GYN 5%, unknown 23%. Ki67 index (available for 18 pts) median 68% (range 30 to >95%). Chemo choice: 17 IRI (77%) and 5 PAC (23%). PEM/IRI was safe based on lead-in. Median number of cycles of therapy administered was 3 (range 0-13). Treatment-related Gr 3 or 4 AE occurred in 7 (32%) of 22 pts overall: 4 (18%) had at least one Gr 3 AE attributed to PEM (1 pt each with pain, ALT increase, or nausea; 2 with fatigue); 7 (32%) had at least one Gr 3/4 AE attributed to chemo (2 with fatigue, 2 with neutropenia; 1 each with pain, ALT increase, hyponatremia, diarrhea, nausea, and/or acute kidney injury). No grade 5 AE. ORR was 9%: PR in 2 pts (9%), SD 3 pts (14%), PD 13 pts (60%); 4 pts (18%) unevaluable (off study before first scheduled scan). Median PFS 2 mo. At last follow-up, 5 pts (23%) were alive with 1 pt still on treatment. Median OS 4 mo. Of 21 pts off treatment, 76% off for PD, 10% off for AE, 14% off for withdrawal of consent/other therapy. Conclusions: PEM + chemotherapy was not effective in this pretreated, biomarker-unselected population of EP-PDNECs arising in different organs. Biomarker studies are planned (Parts A/B). Clinical trial information: NCT03136055.

Safety and efficacy of perioperative cisplatin/gemcitabine (cis/gem) and durvalumab (durva) for operable muscle-invasive urothelial carcinoma (MIUC): SAKK 06/17.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 430-430
Author(s):  
Richard Cathomas ◽  
Sacha Rothschild ◽  
Stefanie Hayoz ◽  
Martin Spahn ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Type I Error ◽  
Checkpoint Inhibitors ◽  
Neoadjuvant Treatment ◽  
Upper Urinary Tract ◽  
Pathological Response ◽  
R0 Resection ◽  
Type I ◽  
Open Label ◽  
Perioperative Morbidity

430 Background: The combination of cisplatin-based chemotherapy with immune checkpoint inhibitors is extensively investigated in urothelial carcinoma. Using this combination in the neoadjuvant setting for patients (pts) with MIUC might improve pathological response rate (PaR: <ypT2N0) but carries the risk of increased perioperative morbidity. Methods: SAKK 06/17 is an open-label single arm phase II trial for pts with operable MIUC cT2-T4a cN0-1. Treatment consists of 4 cycles of neoadjuvant cis/gem q3w in combination with 4 cycles durva 1500mg q3w followed by resection. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival (EFS) at 2 years. 58 pts are needed based on type I error of 10% and a power of 80% for H1 EFS at 2 years ≥ 65% compared to H0 EFS at 2 years ≤ 50%. We report the secondary endoints PaR, pathological complete remission (pCR: ypT0 N0), and safety on the full analysis set (FAS, received at least one dose of durva). Results: 61 pts were included between 7/18 and 9/19 at 12 sites. The FAS consists of 58 pts (79% male, median age 67.5 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage were present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. 95% of pts received all 4 doses of neoadjuvant durva, 81% all 4 cycles of cis/gem and 17% switched to carboplatin. In total grade 3 and 4 adverse events (AE) during neoadjuvant treatment occurred in 48% and 27%, respectively. AEs related to durva were G3 in 7 pts (12%) and G4 in one patient (2%). Resection was performed in 53 pts (91%; 51 radical cystectomy, 2 nephroureterectomy), 4 pts refused surgery and one patient was irresectable due to a frozen pelvis. R0 resection was achieved in 52 pts (98%), one had R1. Postoperative complications included Clavien-Dindo III in 13 pts (24%) and IV in 5 pts (9%). PaR was found in 60% (95% CI 46.0%-73.5%) with 18 pts achieving pCR (34%; 95% CI 21.5%-48.3%) and 14 patients (26%) ypT1/ypTis. Conclusions: The first FAS results for neoadjuvant durvalumab in combination with cis/gem for operable MIUC confirm elevated pathological response rates and demonstrate acceptable safety. Postoperative morbidity is relevant but not exceeding the expected frequency or severity. Clinical trial information: NCT03406650.

Gemcitabine (Gem) and nab-paclitaxel (NP) ± nivolumab (nivo) ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients (Pts) with untreated metastatic pancreatic adenocarcinoma (mPDAC): Phase (Ph) 2 final results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4019-4019
Author(s):  
Mark H. O'Hara ◽  
Eileen Mary O'Reilly ◽  
Robert A. Wolff ◽  
Zev A. Wainberg ◽  
Andrew H. Ko ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Type I Error ◽  
Acute Hepatic Failure ◽  
Tumor Burden ◽  
Clinical Activity ◽  
Tumor Biomarker ◽  
Type I ◽  
Open Label ◽  
Comparison Results ◽  
Biomarker Analysis

4019 Background: Results from a ph1b trial evaluating gem/NP with CD40 agonistic monoclonal antibody APX005M ± nivo demonstrated promising clinical activity in pts with untreated mPDAC (O’Hara 2021). Herein, we report results from the follow-on, randomized (rand) ph2 trial evaluating gem/NP ± nivo ± APX005M. Methods: Pts with untreated mPDAC were rand to 1 of 3 open-label arms: gem/NP/nivo (A), gem/NP/APX005M (B), gem/NP/nivo/APX005M (C). All pts were treated with 1000 mg/m2 gem and 125 mg/m2 NP. Patients received 240 mg nivo in arms A and C and 0.3 mg/kg APX005M (RP2D) IV in arms B and C. Ph1b pts were included in ph2 analyses. 1° endpoint: 1-year OS rate of each arm, compared to a 35% historical OS rate for gem/NP (Von Hoff 2013). Key 2° endpoints: ORR, DCR, DOR, PFS and safety. Tumor and blood were collected for biomarker analysis. Planned enrollment of 35 pts/arm provided 81% power for testing the alternative of 58% OS rate vs 35%, using a 1-sided, 1-sample Z test with 5% type I error. Trial was not powered for cross-arm comparison. Results: 93 pts were rand in ph2 (N = 34, 30, 29 to A, B, C); when ph1b pts included, a total of 105 pts (34, 36, 35) were analyzed for efficacy and 108 pts (36, 37, 35) for safety. Min follow-up was 14 months (mos). Baseline characteristics were balanced across arms, inclusive of tumor burden, presence of liver metastases and stage at initial diagnosis (stage 1-3 vs 4). 1-year OS rate was 57% (1-sided p = 0.007 vs 35% historical rate, 95% lower CI bound = 41%) for A, 51% (p = 0.029, 95% bound = 36%) for B and 41% (p = 0.236, 95% bound = 27%) for C. Median OS and secondary endpoints are listed in Table. TRAE rates were similar across arms and to ph1b. 8 (7%) pts experienced an AE leading to tx discontinuation (6, 1, 1 in A, B, C), 40 (37%) pts experienced a serious TRAE (14, 15, 11 in A, B, C) and 2 pts died due to TRAEs; 1 each in B (acute hepatic failure) and C (intracranial hemorrhage). Conclusions: In this ongoing, seamless ph1b/2 trial of gem/NP ± nivo ± APX005M in pts with mPDAC, antitumor activity was observed in all arms. 1° endpoint of 1-year OS > 35% was met when combining gem/NP with either nivo or APX005M; however, not the combination. Safety was manageable; consistent with ph1b. Detailed multiomic immune and tumor biomarker analyses are underway to elucidate mechanisms of action and inform pt subsets that benefit most from these combinations. Clinical trial information: NCT03214250. [Table: see text]

Phase IIb trial of oral ModraDoc006/r as a tolerable and effective option in comparison with intravenous docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 132-132
Author(s):  
Ulka N. Vaishampayan ◽  
Marianne Keessen ◽  
Neal D. Shore ◽  
Elisabeth I. Heath ◽  
Robert Dreicer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Oral Prednisone ◽  
Objective Response ◽  
Comparable Efficacy ◽  
Point Estimate ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Oral Tablet ◽  
Study Results ◽  
Patient Reported

132 Background: ModraDoc006 is a novel, oral tablet formulation of docetaxel. To enhance bioavailability, it is co-administered with ritonavir (r), an inhibitor of cytochrome P450 3A4 and P-glycoprotein. The oral combination, denoted ModraDoc006/r, has potential advantages in terms of patient convenience, elimination of infusion-related reactions and avoiding prophylactic steroid administration, as well as safety benefits. Safety and preliminary efficacy of ModraDoc006/r in mCRPC were established in a prior phase Ib trial. Methods: This is an open label 1:1 randomized phase IIb trial of ModraDoc006/r bi-daily once weekly (BIDW) regimen versus IV docetaxel 75 mg/m2 q day 21. Initially, BIDW 30-20 mg ModraDoc006 combined with 200-100 mg ritonavir was administered on days 1, 8 and 15 of a 21-day cycle. After 39 patients, the dose of ModraDoc006 was reduced to 20-20 mg BIDW to improve GI tolerability. All patients received 5 mg oral prednisone BID. Imaging is obtained every 8-9 weeks for the first 24 weeks, every 12 weeks thereafter. Initially mCRPC patients with RECIST 1.1 measurable disease were eligible; this was amended to evaluable disease per Prostate Cancer Working Group 3 (PCWG3) to allow for wider recruitment. No prior taxane therapy is allowed. The primary efficacy endpoint is radiographic progression free survival (rPFS) per PCWG3 criteria. Secondary objectives include objective response rate, PSA-PFS, time to skeletal related events, disease control rate, duration of response and safety. Patient reported outcomes, QoL and FACT-P questionnaires are assessed. It is expected that ModraDoc006/r will be as effective as IV docetaxel. A sample size of approximately 50 evaluable patients per arm will provide a point estimate of the primary endpoint of rPFS for this study. Results: At the data cut-off of 30 Nov 2020, 90 patients were enrolled in US and EU: 44 patients had been randomized to IV docetaxel and 46 to ModraDoc006/r, with 58 patients currently on treatment. Preliminary PSA response rates and rPFS were noted to be comparable in both treatment arms. ModraDoc006/r was mainly associated with mild and reversible GI-toxicity, of which grade and incidence were reduced at 20-20 mg compared to the initial dose-level of 30-20 mg ModraDoc006. Myelosuppression and neurotoxicity were low to negligible in the ModraDoc006/r arm, with low accompanying levels of alopecia. Conclusions: Adverse events of cytopenias and alopecia were lower with ModraDoc006/r, and preliminary efficacy appears comparable in both arms. Oral chemotherapy option has become critically important during the COVID-19 pandemic. Preliminary data reveals that ModraDoc006/r is an attractive oral option in mCRPC with favorable toxicity profile and comparable efficacy. Clinical trial information: NCT04028388.

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