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

scholarly journals Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000798
Author(s):  
Lu Xie ◽  
Jie Xu ◽  
Xin Sun ◽  
Wei Guo ◽  
Jin Gu ◽  
...  
Keyword(s):  
Pulmonary Metastases ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
High Grade Osteosarcoma

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.MethodsThis open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.Results43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.ConclusionsAlthough the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.Trial registration numberNCT03359018.

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.

Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): The phase II AVETUX-CRC trial (AIO KRK 0216).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3620-TPS3620 ◽  
Author(s):  
Alexander Stein ◽  
Mascha Binder ◽  
Carsten Bokemeyer ◽  
Salah Eddin Al Batran ◽  
Axel Hinke ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mismatch Repair ◽  
Phase Ii ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Type I ◽  
Translational Research Program ◽  
Clinical Trial Information

TPS3620 Background: Inhibition of the PD-1/L1 axis has shown to improve survival as single agent in a variety of tumor types. The efficacy of single agent PD-1/L1 inhibition in patients with treatment refractory MCRC seems to be limited to hypermutated tumors characterized by mismatch repair deficiency. 1st line chemotherapy (e.g. FOLFOX) with cetuximab for patients with RAS/BRAF wildtype MCRC result in objective response rates of about 60%, thus substantial antigen release will likely occur triggering immune control. Furthermore, the induction of immunogenic cell death has been recently shown for cetuximab-based regimen. Thus, the evaluation of FOLFOX and cetuximab in combination with avelumab in 1st line MCRC is of particular interest. Methods: AVETUX is a single arm exploratory phase II investigator initiated trial. Patients with RAS/BRAF wildtype MCRC will be included independent of mismatch repair status to receive mFOLFOX6 and cetuximab in combination with avelumab (10mg/kg from day 1 of cycle 2 onwards). Treatment with avelumab is limited to a maximum of 18 months. Primary endpoint is 12month progression-free survival rate, which should be increased from 40% to 57%, with type I error of 10% and 80% power, leading to a sample size of 43 patients. An early stopping rule will be applied in case of an increase in toxicity after the first 15 patients received at least two months of treatment. The trial is flanked by a large translational program including immunoprofiling to determine and correlate the respective immune response signatures with clonal dynamics (RAS/EGFR). Recruitment will start in 11 German sites early 2017. Clinical trial information: EudraCT No 2016-004434-26. Conclusion: The AVETUX trial will determine the feasibility and early efficacy of FOLFOX and cetuximab combined with avelumab in 1st line MCRC. The translational research program will shed light on the potential mode of action of this novel combination. Clinical trial information: 2016-004434-26.

Interim analysis of IMMUNEBOOST-HPV: A multicenter, randomized, open label, phase II study evaluating the feasibility, and tolerance of neoadjuvant nivolumab in high-risk HPV driven oropharynx cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6037-6037
Author(s):  
Haitham Mirghani ◽  
Caroline Even ◽  
Alicia Larive ◽  
Jerome Fayette ◽  
Karen Benezery ◽  
...  
Keyword(s):  
Type I Error ◽  
Data Monitoring Committee ◽  
Smoking History ◽  
Type I ◽  
Open Label ◽  
Hpv Dna ◽  
Neoadjuvant Immunotherapy ◽  
Open Label Phase ◽  
High Risk Hpv ◽  
Type 2 Error

6037 Background: Among HPV-positive Oropharyngeal Cancer (OPC) patients (pts), some has a less favorable prognosis (T4, N2/N3, smokers >10 pack-year [p/y]). We assume that neoadjuvant immunotherapy might improve their oncological outcomes, so we tested nivolumab (N) prior to ChemoRadiaTion (CRT). Methods: The study population is restricted to HPV positive OPC pts (both p16+ & HPV-DNA+) with advanced disease (T4, N2/N3) or a smoking history >10 p/y. Pts were randomly allocated 1:2 to receive either cisplatin-based CRT (n=20) or 2 cycles of N 240 mg followed by CRT (n=41). The Primary Endpoint (PE) is the rate of pts who can receive Full Treatment in Due Time (FTDT), according to these criteria: a) 2 N infusions on day 1 and on day 14-16 b) CRT started between days 28-37 after the 1st N infusion c) No RT break ≥1 week d) RT dose received >95% of theoretical dose e) Cisplatin dose received ≥200 mg/m² To achieve FTDT, all criteria are required in the Experimental Arm (EA) while only criteria c), d), and e) are required in the Control Arm (CA). In the EA, the trial was designed in 2 steps, with FTDT rate of 88% considered as inacceptable versus an alternative of 98%, a type I error of 0.10, and a type 2 error of 0.08. As per protocol, patient accrual was temporarily suspended after inclusion of 19 pts in the EA (1st step) and results were reviewed by an Independent Data Monitoring Committee (IDMC). To resume pts’ inclusion, FTDT had to be achieved in 18 pts in the EA. Results: From 07/2019 to 09/2020, 30 pts were enrolled including 11 in the CA (demographics are summarized in table). 2 pts in the EA did not reach the PE. For the 1st patient, the cisplatin dose was <200 mg/m2 due to grade 1 hearing loss and grade 2 tinnitus (1st cycle: 100 mg/m2, 2nd cycle: 80 mg/m2, no 3rd cycle). For the 2nd patient, CRT began at D38 due to logistical issues (maintenance of RT devices). As this delay was unrelated to N or to patient's condition, the IDMC considered that the inclusions could resume for the 2nd step. 7 N-related Adverse Events (AE) were reported in 4 pts including 3 serious AE (ankylosing spondylitis flare-up, colitis, diabetic ketoacidosis). Conclusions: Neoadjuvant N before CRT seems feasible for the treatment of OPC pts. The trial has reopened to inclusion as recommended by the IDMC. Clinical trial information: NCT03838263. [Table: see text]

Phase II study of dovitinib in first-line metastatic or nonresectable primary adrenocortical carcinoma (ACC): SOGUG study 2011-03.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4688-TPS4688
Author(s):  
Paula Jimenez ◽  
Marta Guix ◽  
Nuria Lainez Milagro ◽  
Luis Leon Mateos ◽  
Maria Jose Mendez Vidal ◽  
...  
Keyword(s):  
Phase Ii ◽  
Type I Error ◽  
Sample Size Calculation ◽  
Growth Factor Receptor ◽  
Collaborative Group ◽  
Type I ◽  
Open Label ◽  
Prior Therapy ◽  
Power Of The Test ◽  
Open Label Phase

TPS4688 Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, among other tyrosin kinases, the fibroblast growth factor receptor (FGFR). Since this pathway has been proposed to play a major role in ACC, we aim to test the clinical efficacy of dovitinib in this tumor. Methods: An open label phase II trial has been designed in patients with advanced non-resectable ACC. The objective will be to obtain at least a 15% response rate according to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 patients would need to be included in the first stage to demonstrate a treatment efficacy of at least 15%. Sample size calculation was done based on the following parameters, probability of Type I error α = 0.05, power of the test (1 - β) = 0.8. Main inclusion criteria are advanced non-resectable disease and no prior therapy (other than mitotane). Dovitinib scheduled dose matches currently employed standard in the drug development (500mg daily for 5 days then 2 days off) for 6 months. If clinical benefit is obtained longer treatment will be allowed for particular patients. Since this is an extremely unfrequent disease 7 institutions, members of the SOGUG (Spanish Oncology Genitourinary Group), will participate. The active support of a big collaborative group will guarantee candidate patients to be refereed to such institutions. Starting January 26th 2012 recruitment is scheduled to last around 12 months. A translational research, including whole exome analysis, will be performed in order to improve our scarce knowledge of ACC.

First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 546-546 ◽  
Author(s):  
David F. McDermott ◽  
Jae-Lyun Lee ◽  
Marek Ziobro ◽  
Rustem Airatovich Gafanov ◽  
Vsevolod Borisovich Matveev ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Objective Response ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
End Points ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Combined Positive Score

546 Background: PD-1/L1 pathway inhibitors are effective in clear cell (cc)RCC, but efficacy of PD-1 inhibitors (or any therapy) in nccRCC has not been established. KEYNOTE-427 is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced ccRCC (cohort A) and nccRCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed nccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts were followed after PD for overall survival. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Secondary end points included duration of response (DOR) and population description by International Metastatic RCC Database Consortium (IMDC) risk. Exploratory end points: ORR by histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). 68% of patients were at intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At a median follow-up duration of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CRs, 33 [20%] PRs); median DOR was not reached. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified nccRCC. ORR (95% CI) was 28.3% (16.8-42.3) with favorable and 23.2% (15.8-32.1) with intermediate/poor IMDC risk and 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS<1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts; 6% discontinued due to TRAEs. 6 pts died due to AEs, 2 of which were TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in nccRCC, especially with papillary or unclassified histology. Safety profile of pembro was generally as expected. Clinical trial information: NCT02853344.

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.

KEYNOTE-427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non‒clear cell renal cell carcinoma (NCC-RCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4569-4569 ◽  
Author(s):  
Jae-Lyun Lee ◽  
Marek Ziobro ◽  
Rustem Gafanov ◽  
Vsevolod Borisovich Matveev ◽  
Cristina Suarez ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Objective Response ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Sarcomatoid Differentiation

4569 Background: Efficacy of PD-1 inhibitors (or any therapy) in NCC-RCC has not been established. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced clear cell RCC (cohort A) and NCC-RCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed NCC-RCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Additional end points: duration of response (DOR), population description by sarcomatoid differentiation, histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26); 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At median follow-up of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CR, 33 [20.0%] PR). Median DOR was not reached. For responding pts, 81.5% had a response ≥6 mo. 12-mo PFS and OS rates were 22.8% and 72.0%, respectively. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified NCC-RCC; for responding pts, 82.1%, 50.0%, and 87.5% had a response ≥6 mo, respectively. Median DOR was not reached in any group. ORR (95% CI) was 44.7% (28.6-61.7) for pts with sarcomatoid differentiation (n = 38). ORR (95% CI) was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS < 1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts. 6 pts died of AEs, 2 of TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in NCC-RCC, especially with papillary or unclassified histology. Safety profile of pembro was as expected. Updated data with additional follow-up will be presented. Clinical trial information: NCT02853344.

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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

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