Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) patients.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 510-510
Author(s):  
Karim Chamie ◽  
Sam Chang ◽  
Mark L. Gonzalgo ◽  
Eugene V. Kramolowsky ◽  
Wade J. Sexton ◽  
...  
Keyword(s):  
T Cells ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Treatment Options ◽  
Complete Response ◽  
Clinical Results ◽  
Low Grade ◽  
Treatment Schedule ◽  
Open Label ◽  
Muscle Invasive

510 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase Ib data in BCG-naive patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. An open-label, 3 cohort multicenter phase II/III study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. We report here the interim analysis of Cohort A, BCG-unresponsive (CIS) [with or without Ta or T1 disease], as of December 2020 data cutoff. Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A of this phase II/III study is incidence of complete response (CR) of CIS at any time. Results: To date, 80 patients have enrolled in cohort A of this phase II/III trial. Evaluable analysis at this time shows CR rate at any time of 72% (N=51/71); for patients achieving CR, the probability of maintaining a CR for 12 months is 59%, with a median duration of complete response of 19.2 (7.6, 26.4) months. Low-grade treatment related AEs include dysuria, hematuria, and pollakiurua (all 16%), urgency (14%), and bladder spasm (8%), all other AEs were seen at 6% or less. A total of 9 subjects experienced at least 1 treatment emergent SAE (Severe Adverse event), the SAE rate is 1% for any given AE. No treatment emergent SAE’s were considered treatment related. No immune related SAE’s have been seen. To date, 10/80 (12.5%) patients proceeded to cystectomy in this BCG unresponsive population. Conclusions:With a CR rate of 72%, N-803 has met its primary endpoint with 59% probability of CR patients maintaining CR for at least 12 months. With the observed strong efficacy and an SAE rate of 1%, N-803 represents a novel treatment option for BCG unresponsive CIS with a favorable benefit:risk ratio, in a therapeutically challenging disease. Clinical trial information: NCT03022825.

A multicenter clinical trial of intravesical BCG in combination with ALT-803 in patients with BCG-unresponsive non-muscle invasive bladder cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS544-TPS544 ◽  
Author(s):  
Karim Chamie ◽  
Amirali Salmasi ◽  
Charles Joel Rosser ◽  
Amy Rock ◽  
Lydia Ferguson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Complete Response ◽  
Salvage Chemotherapy ◽  
Low Grade ◽  
High Grade ◽  
Open Label ◽  
Intravesical Bcg ◽  
Muscle Invasive ◽  
Group B

TPS544 Background: BCG unresponsive NMIBC includes patients with persistent high-grade disease or recurrence within 6 months of receiving at least two courses of BCG; or T1 high-grade disease at the first evaluation following BCG induction alone. The recommendation after failing BCG in patients suitable for surgery is cystectomy or for unwilling/unfit patients, salvage chemotherapy or immunotherapy (administered with limited success). This highlights a critical need for novel preservation therapies to facilitate a better quality of life and reduce health-care costs for patients who are unresponsive to BCG (Correa 2015, Dalbagni 2006, Dinney 2013, Kamat 2017). Altor BioScience has initiated a phase II clinical study in BCG unresponsive patients to expand on promising data collected from a compassionate use patient who remains disease free more than 2.5 years after ALT-803 plus BCG treatment for refractory NMIBC (Huang 2017). Methods: This is a Phase II, open-label, single-arm, multicenter study of intravesical BCG plus ALT-803 in patients with BCG unresponsive high grade NMIBC. Group A will enroll patients who have histologically confirmed presence of CIS [with or without Ta or T1 disease]. Group B will enroll patients who have histologically confirmed high-grade Ta or T1 disease (in the absence of CIS). All patients will receive BCG plus ALT-803 weekly for 6 consecutive weeks. A cystoscopy will be performed at Week 12. Patients with no disease or low-grade Ta will receive a maintenance course of therapy (3 weekly instillations of BCG plus ALT-803). Patients with residual CIS and/or high-grade Ta will receive a re-induction course of therapy. Presence of Ta will require a TURBT. Patients with greater than or equal to T1 disease or new CIS will be deemed treatment failures. Patients with a Complete Response (CR) or low-risk disease at Months 6, 9 and 12 are eligible for continued BCG plus ALT-803 maintenance. Patients will be followed for recurrence, progression, and survival. The primary endpoint is to assess complete response (CR; absence of lesions on cystoscopy or negative, for cause, biopsies along with negative urine cytology) of CIS at six months. Enrollment is underway. Clinical trial information: NCT03022825.

Short Course Radiotherapy Concomitant with Temozolomide in GBM Patients: A Phase II Study

2017 ◽  
Vol 103 (5) ◽  
pp. 457-463 ◽  
Author(s):  
Laura Fariselli ◽  
Lucia Cuppini ◽  
Paola Gaviani ◽  
Marcello Marchetti ◽  
Valentina Pinzi ◽  
...  
Keyword(s):  
Total Dose ◽  
Phase Ii ◽  
Local Control ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Treatment Schedule ◽  
Open Label ◽  
Macdonald Criteria ◽  
Secondary Endpoints ◽  
Group B

Purpose Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM. Methods This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day. Results The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS. Conclusions To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation.

A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4146-TPS4146
Author(s):  
Ignacio Matos Garcia ◽  
Enrique Grande ◽  
Rocio Garcia-Carbonero ◽  
Carlos Lopez ◽  
Alexandre Teule ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Tumor Growth Rate ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Tumor Load

TPS4146 Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue. Clinical trial information: 2016-002858-20.

A phase II study of oxaliplatin reintroduction in patients pretreated with oxaliplatin and irinotecan for advanced colorectal cancer (RE-OPEN study).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 758-758
Author(s):  
Mitsukuni Suenaga ◽  
Nobuyuki Mizunuma ◽  
Satoshi Matsusaka ◽  
Eiji Shinozaki ◽  
Masato Ozaka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Stable Disease ◽  
Tumor Response ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Treatment Start

758 Background: Re-introduction of oxaliplatin (L-OHP) for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy regimens including L-OHP, irinotecan (CPT-11), and fluorouracil was thought to be effective approach. We performed a single arm, open-label phase II study (UMIN ID: 000004884), and the reported results of interim analysis were promising. Methods: Patients with prior chemotherapy including L-OHP and CPT-11 achieved tumor response or stable disease during prior L-OHP based therapy, and 6 months or over from confirmed progression disease during previous L-OHP based therapy was eligible for this study. Patients received FOLFOX regimens every two weeks. Primary endpoint was disease control rate (DCR) after 12 weeks of treatment start. Tumor response was evaluated by RECIST v1.1, and DCR was defined as complete response (CR), partial response (PR) or stable disease. This trial followed a Simon’s two-stage minimax design. Assuming the expected and threshold DCR after 12 weeks of treatment start would be 40% and 20%, 33 patients (18 in Step I and 15 in Step II) were required with a one sided α-level of 5% and a power of 80%. Results: Between February 2011 and August 2013, 33 patients were enrolled in this study. Characteristics of patients were as follows (n=33): median age of 62 years (35-77); male/female: 19/14; ECOG PS0: 84.8%; and colon/rectum: 14/19. All patients received mFOLFOX6 regimen. The DCR after 12 weeks of treatment start was 39.4% (95% CI: 21.8-57.0%), and the primary endpoint was met. The response Rate (CR or PR) was 6.1%. The median number of courses of chemotherapy was five, and the median total dose of L-OHP was 366.9 mg/m2. The median progression free survival was 98 days and the median overall survival was 300 days. The incidence of allergic reaction was 24.4% and peripheral neuropathy was 90.9%, graded as mild to moderate events. There were no other severe adverse events and treatment related deaths. Conclusions: Reintroduction of L-OHP was effective and could be a new salvage option for patients with mCRC refractory to previous L-OHP based therapy. Clinical trial information: 000004884.

scholarly journals Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study

2018 ◽  
Vol 36 (23) ◽  
pp. 2405-2412 ◽  
Author(s):  
Ajay K. Gopal ◽  
Stephen J. Schuster ◽  
Nathan H. Fowler ◽  
Judith Trotman ◽  
Georg Hess ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Adverse Events ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Complete Response ◽  
T Cell Subsets ◽  
Interleukin 12 ◽  
Open Label ◽  
End Point

Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee–assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.

Phase II clinical trial of novel agent PBI-05204 in patients with metastatic pancreatic adenocarcinoma (mPDA).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 698-698
Author(s):  
Marc Thomas Roth ◽  
Dana Backlund Cardin ◽  
Erkut Hasan Borazanci ◽  
Margaux Steinbach ◽  
Vincent J. Picozzi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tumor Burden ◽  
Nerium Oleander ◽  
Orthotopic Model ◽  
Open Label

698 Background: Survival statistics for mPDA are dismal and with limited treatment options novel agents are needed to improve disease outcomes. PBI-05204 (Phoenix Biotechnology, Inc., San Antonio, TX) is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract’s major cytotoxic component, has demonstrated anti-tumor activity in various tumor cell lines. In a human PDA orthotopic model, this preparation reduced tumor burden as monotherapy. Pharmacodynamic studies suggest that PBI-05204’s mechanism of action is through inhibition of the PI3k/Akt/mTOR pathway. Methods: A phase II single-arm, open-label study to determine the efficacy of PBI-05204 in patients (pts) with mPDA refractory to standard therapy was conducted. The primary endpoint was overall survival (OS) with the hypothesis that 50% of pts would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Pts received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or pt withdrawal. Radiographic response was assessed every two cycles. Results: Forty-one pts were enrolled; two never received treatment and one was found to have a neuroendocrine tumor after pathological re-evaluation, leaving 38 pts for analysis. Median age at time of enrollment was 65.0 years. The median time from initial diagnosis to treatment was 16.9 months. The primary reason for withdrawal was PD (45.2%). Ten pts were alive at 4.5 months (26.3%) with a mPFS of 56 days (corresponding to first restaging). One objective response (2.6%) was observed for 162 days. Grade ≥3 treatment-emergent adverse events occurred in 63.2% of pts with the most common attributed to drug (all grades) being fatigue (36.8%), vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Conclusions: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate an efficacious role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy, such as temozolomide, and radiotherapy. A randomized Phase II trial is currently being designed. Clinical trial information: NCT02329717.

Preliminary phase 2 clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4561-4561 ◽  
Author(s):  
Karim Chamie ◽  
John H. Lee ◽  
Amy Rock ◽  
Peter R. Rhode ◽  
Patrick Soon-Shiong
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Primary Endpoint ◽  
Response Assessment ◽  
Complete Response ◽  
Invasive Bladder Cancer ◽  
High Grade ◽  
Phase 2 ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

4561 Background: Patients with non-muscle-invasive bladder cancer (NMIBC) unresponsive to BCG therapy have limited treatment options. N-803 (also known as ALT-803) is an IL-15-based immunostimulatory protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase Ib data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Methods: An open-label, single-arm multicenter Phase 2 study of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. The study has two cohorts: Cohort A, patients with BCG-unresponsive carcinoma in situ (CIS) [with or without Ta or T1 disease] and Cohort B, patients with BCG-unresponsive high-grade Ta/T1 disease. All treated patients receive intravesical N-803 plus BCG, similar to a standard induction and maintenance treatment schedule. The primary endpoint for Cohort A is incidence of complete response (CR) of CIS at any time, and the primary endpoint for Cohort B is disease-free rate at 12 months. Results: To date, forty-six patients have enrolled in this phase 2 trial (Cohort A (CIS), n = 23, Cohort B (Papillary), n = 23). Of eleven evaluable patients in Cohort A, nine patients (82%) have a reported CR. In addition, seven out of nine (78%) patients in Cohort A demonstrated CR at their 6-month response assessment. Of thirteen evaluable patients in Cohort B, ten patients (77%) showed no evidence of recurrence at their 3-month response assessment; of these, none (0/8) evaluated past 3 months have had disease recurrence. Three serious adverse events (AEs) have been reported (E coli infection, anemia, and bacteremia), with no immune-related AEs. Conclusions: Nine out of eleven (82%) patients with BCG-unresponsive CIS of the bladder demonstrated a complete response. Ten out of thirteen patients with BCG-unresponsive papillary NMIBC show no evidence of disease at first assessment. Intravesical N-803 plus BCG was well-tolerated and no patients experienced immune-related AEs. Clinical trial information: NCT03022825.

γδ T cells for immune therapy of patients with lymphoid malignancies

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Martin Wilhelm ◽  
Volker Kunzmann ◽  
Susanne Eckstein ◽  
Peter Reimer ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Low Dose ◽  
Γδ T Cells ◽  
Low Grade ◽  
Treatment Schedule ◽  
Γδ T Cell

Abstract There is increasing evidence that γδ T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent γδ T cell stimulatory compounds that induce cytokine secretion (ie, interferon γ [IFN-γ]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of γδ T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of γδ T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 × 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, γδ T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of γδ T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of γδ T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of γδ T cells responded to treatment, indicating that γδ T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that γδ T-cell–mediated immunotherapy is feasible and can induce objective tumor responses. (Blood. 2003;102:200-206)

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