scholarly journals P1.01-110 Novel Regimens Versus Standard-of-Care in NSCLC: A Phase II, Randomized, Open-Label, Platform Trial Using a Master Protocol

2019 ◽  
Vol 14 (10) ◽  
pp. S404-S405
Author(s):  
D. Spigel ◽  
M. Garassino ◽  
B. Besse ◽  
A. Sacher ◽  
M. Barve ◽  
...  
Keyword(s):  
Phase Ii ◽  
Standard Of Care ◽  
Open Label

scholarly journals High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial

2021 ◽  
Author(s):  
Fiona V Cresswell ◽  
David B Meya ◽  
Enock Kagimu ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Geometric Mean ◽  
Standard Of Care ◽  
Hiv Positive ◽  
High Dose ◽  
Open Label ◽  
Dose Oral ◽  
Csf Levels

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

scholarly journals A randomized, multicentre, open-label phase II proof-of-concept trial investigating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19: the Donated Antibodies Working against nCoV (DAWn-Plasma) trial

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Timothy Devos ◽  
Tatjana Geukens ◽  
Alexander Schauwvlieghe ◽  
Kevin K. Ariën ◽  
Cyril Barbezange ◽  
...  
Keyword(s):  
Treatment Group ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Active Treatment ◽  
Standard Of Care ◽  
Active Treatment Group ◽  
Proof Of Concept ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase

Abstract Background The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of patients having recovered from SARS and severe influenza to patients actively having the disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. Methods DAWn-Plasma is a multicentre nation-wide, randomized, open-label, phase II proof-of-concept clinical trial, evaluating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19 in Belgium. Patients hospitalized with a confirmed diagnosis of COVID-19 are eligible when they are symptomatic (i.e. clinical or radiological signs) and have been diagnosed with COVID-19 in the 72 h before study inclusion through a PCR (nasal/nasopharyngeal swab or bronchoalveolar lavage) or a chest-CT scan showing features compatible with COVID-19 in the absence of an alternative diagnosis. Patients are randomized in a 2:1 ratio to either standard of care and convalescent plasma (active treatment group) or standard of care only. The active treatment group receives 2 units of 200 to 250 mL of convalescent plasma within 12 h after randomization, with a second administration of 2 units 24 to 36 h after ending the first administration. The trial aims to include 483 patients and will recruit from 25 centres across Belgium. The primary endpoint is the proportion of patients that require mechanical ventilation or have died at day 15. The main secondary endpoints are clinical status on day 15 and day 30 after randomization, as defined by the WHO Progression 10-point ordinal scale, and safety of the administration of convalescent plasma. Discussion This trial will either provide support or discourage the use of convalescent plasma as an early intervention for the treatment of hospitalized patients with COVID-19 infection. Trial registration ClinicalTrials.govNCT04429854. Registered on 12 June 2020 - Retrospectively registered.

scholarly journals High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study)

2018 ◽  
Vol 3 ◽  
pp. 83 ◽  
Author(s):  
Fiona V. Cresswell ◽  
Kenneth Ssebambulidde ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
Abdul Musabire ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Phase Ii ◽  
Controlled Trial ◽  
Standard Of Care ◽  
Hiv Positive ◽  
Current Standard ◽  
Open Label ◽  
Dose Oral ◽  
Randomised Controlled ◽  
Positive Population

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration.  With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24th April 2018)

Perioperative chemoimmunotherapy with durvalumab (Durva) in combination with cisplatin/gemcitabine (Cis/Gem) for operable muscle-invasive urothelial carcinoma (MIUC): Preplanned interim analysis of a single-arm phase II trial (SAKK 06/17).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 499-499 ◽  
Author(s):  
Richard Cathomas ◽  
Ulf Petrausch ◽  
Stefanie Hayoz ◽  
Martina Schneider ◽  
Julian Andreas Schardt ◽  
...  
Keyword(s):  
Postoperative Complications ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Interim Analysis ◽  
Checkpoint Inhibitors ◽  
Neoadjuvant Treatment ◽  
Standard Of Care ◽  
Operation Technique ◽  
Open Label ◽  
Pathological Complete Remission

499 Background: Cisplatin-based neoadjuvant chemotherapy followed by surgery is the standard of care for patients (pts) with MIUC but relapse rates remain high. Immune checkpoint inhibitors have demonstrated efficacy in advanced urothelial carcinoma (UC). We hypothesize that the integration of the PD-L1 inhibitor durvalumab into perioperative management of MIUC improves outcome. Methods: SAKK 06/17 is an open label single arm phase II study including 61 pts. Operable MIUC cT2-T4a cN0-1 pts without contraindication for Cis were eligible. Four cycles of preoperative Cis/Gem q3w are administered in combination with 4 cycles Durva 1500mg q3w starting at cycle 2. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival at 2 years. We report a preplanned interim analysis of the secondary endpoints safety, pathological complete remission ypT0 N0 (pCR,) and pathological response rate (PaR, defined as ≤ypT1N0) on the first 30 resected pts. Results: Among 34 eligible pts (27M, 7F; median age 70, range 41-81 years) included from 07/18 – 02/19, 33 pts (97%) had primary bladder cancer and 1 pt had upper tract UC. Clinical T2, T3, T4 and TxN1 stage were present at diagnosis in 68%, 18%, 15% and 15%, respectively. Four cycles of chemo-immunotherapy were completed per protocol in 34 pts (100%). No tumor progression was noted at preoperative restaging. AE related to Durvalumab were G3 in 5 pts (15%) and G4 in 3 pts (9%). Surgery was performed as planned in 30 pts (88%), 3 pts refused surgery and 1 pt had a frozen pelvis. Operation technique was open in 20 pts (67%) and laparoscopic/robot-assisted in 10 pts (33%). Postoperative complications included Clavien-Dindo III in 6 pts (20%) and IV in 2 pts (7%) with infections being most common (5 pts, 17%). pCR was found in 9 pts (30%) and additional 6 pts (20%) had ypT1/ypTis for a PaR of 50%. Conclusions: The combination of Cis/Gem and Durva as neoadjuvant treatment for MIUC is feasible with manageable toxicities and pCR and PaR rates in the expected range. The rate of postoperative complications warrants further close follow up. Clinical trial information: 2017-003565-10.

Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2553-2553 ◽  
Author(s):  
Nataliya Volodymyrivna Uboha ◽  
Mohammed M. Milhem ◽  
Christina Kovacs ◽  
Alpesh Amin ◽  
Andrea Magley ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Hematologic Malignancies ◽  
Open Label ◽  
Bayesian Hierarchical ◽  
Dual Blockade ◽  
Tumor Types ◽  
Clinical Trial Information

2553 Background: Spartalizumab and LAG525 are monoclonal antibodies targeting PD-1 and LAG-3, respectively. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor activity in preclinical models. Here we describe preliminary efficacy of spartalizumab + LAG525 across seven tumor types. Methods: Phase II, open-label, parallel-cohort study was conducted in pts with solid or hematologic malignances relapsed and/or refractory to standard-of-care therapies. Prior immunotherapy was prohibited. LAG525 (400 mg) and spartalizumab (300 mg) were dosed intravenously every 3 weeks. Primary endpoint was clinical benefit rate at 24 weeks (CBR24), assessed using a Bayesian hierarchical model-based futility analysis. Posterior probability that clinical benefit exceeds historical control (Pr) was estimated to determine futility at interim against prespecified thresholds. Results: As of January 7 2019, 76 pts received spartalizumab + LAG525; 72 pts were eligible for analysis (Table). The Pr cut-off for all arms was > 0.70. Hence, neuroendocrine tumors (NET), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) cohorts all met the expansion criteria with Pr of 0.971, 0.975 and 0.804 respectively. CBR24 were as follows; NET: 0.86, SCLC: 0.27, DLBCL: 0.43. Prostate, sarcoma and ovarian cohorts did not meet the expansion criterion (Pr > 0.70) but were not declared futile; enrollment was paused pending results of next analysis. Gastroesophageal (GE) cancer cohort was stopped for futility due to Pr (0.071) below the futility threshold. Conclusions: Spartalizumab and LAG525 showed promising activity in NET, SCLC and DLBCL that met expansion criteria. The GE cohort was declared futile. Remaining cohorts are paused pending further analysis. Clinical trial information: NCT03365791. [Table: see text]

Combination of radiomic and biomarker signatures as exploratory objective in a phase II trial with intratumoral BO-112 plus pembrolizumab for advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9586-TPS9586
Author(s):  
Ivan Marquez-Rodas ◽  
Stéphane Dalle ◽  
Eduardo Castanon ◽  
Miguel F. Sanmamed ◽  
Ana Maria Arance ◽  
...  
Keyword(s):  
Phase Ii ◽  
Human Study ◽  
Standard Of Care ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Radiologic Findings

TPS9586 Background: Intratumoral immunotherapies are gaining interest in oncology, particularly in melanoma. These therapies, however, have faced some issues. For instance, standard response criteria do not accurately describe tumor burden, and responses may differ for injected/non injected lesions. Besides, target lesions may become non evaluable. Biomarkers provide interesting information for these therapies. In addition, some radiomic signatures have been associated with CD-8 infiltration. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that mimics a viral infection, mobilizing the immune system and changing tumor microenvironment. Clinical data are available from a first-in-human study, which showed ORR of 11% and DCR of 46% in patients who had developed progressive disease on immunotherapy. In patients with melanoma, this ORR was 20%. A phase 2 clinical study of BO-112 with pembrolizumab in patients with liver metastases from digestive tumors is ongoing. Both studies brought up data regarding how some biomarkers are increased after a single dose of BO-112 and correlated with responses. In this phase II study in patients with pretreated melanoma (NCT04570332), we will prospectively assess CD-8 and PD-L1 by immunohistochemistry, which will be compared with multi-parametric radiologic findings and correlated with clinical benefit. In addition, retrospective DNA sequencing will be performed. This kind of exploratory analysis in intratumoral immunotherapies might be key to identify predictive and prognostic factors. Methods: Phase 2, single arm, open label study of BO-112 with pembrolizumab in patients with advanced melanoma. BO-112 is administered once weekly (QW) in 1 to 8 tumor lesions, total dose 1-2 mg (depending on the number of injected lesions), for the first 7 weeks and then once every three weeks (Q3W); pembrolizumab 200 mg will be administered Q3W. Key eligibility criteria: advanced cutaneous or mucosal melanoma; patients must have progressed on or after treatment with an antiPD-1/L1 mAb; at least one measurable lesion amenable for weekly IT injection. Primary efficacy variable is ORR by RECIST 1.1, assessed by independent central radiologist (QUIBIM Precision platform). A 1-sided alpha of 4.19% and power of 81.8% are used. If less than 8 patients out of 40 have ORR, the study will not meet the statistical bar. Secondary endpoints include clinical activity by RECIST1.1 and iRECIST, overall survival, safety and PKs. Exploratory objectives include itRECIST and evaluation of CD-8 and PD-L1 expression by immunohistochemistry (Pangaea laboratory), which will be correlated with radiomic signatures (first order and second order) from standard-of-care computed tomography (CT) images. Enrollment is open and 1 of planned 40 patients has been enrolled. Nineteen sites are planned to participate. Clinical trial information: NCT04570332.

A phase II study of palbociclib for recurrent or refractory advanced thymic epithelial tumor (KCSG LU17-21).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8576-8576
Author(s):  
Myung-Ju Ahn ◽  
Hyun Ae Jung ◽  
Miso Kim ◽  
Joo-Hang Kim ◽  
Yoon Hee Choi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Combination Chemotherapy ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Median Number ◽  
Genetic Alterations ◽  
Anterior Mediastinum ◽  
Open Label ◽  
Epithelial Tumor ◽  
Thymic Epithelial Tumors

8576 Background: Thymic epithelial tumors (TETs) are rare but the most common tumor of the anterior mediastinum. Platinum-based combination chemotherapy is standard of care which is associated with a 50%-90% overall response rate (ORR) in metastatic disease. However, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with cell cycle including pRB, p16INK4A, and cyclin D1 are commonly observed in TETs. Based on these results, we conducted a phase II trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. Methods: This is a phase II multicenter, open-label, single arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapy. Patients receive oral palbociclib 125mg daily for 21 days followed by a 7-day break. The primary endpoint was the progression-free survival (PFS) rate at 6 months (H0 = 30% vs H1 = 48%). Results: Between August 2017 and October 2019, 48 patients were enrolled. The median number of previous chemotherapy was 1 (range: 1-4) and 21 (43.7%) of 48 patients received thymectomy. By WHO classification, Type A (n = 1), Type B1 (n = 2), Type B2 (n = 8), Type B3 (n = 13), Type C (n = 23), and unknown (n = 1). With medial follow-up of 14.5 months (range 0.8-38.2), the median cycle of palbociclib was 10 (range 1-40). The PFS at 6 months was 60% and the median PFS was 11.0 months (95% CI: 4.6-17.4). Six of 48 patients (12.5%) achieved partial response. The median overall survival was 26.4 months (95% CI: 17.4-35.4). The most common adverse events of any grade included neutropenia (62.5%), anemia (37.5%) and thrombocytopenia (29.1%). Conclusions: Palbociblib monotherapy is well tolerable and encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy. Updated results will be presented. Clinical trial information: NCT03219554.

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