A randomized, double-blind, placebo-controlled investigation of the safety, tolerability and pharmacokinetics of 1% SPL7013 nasal spray in healthy volunteers when administered four times a day for 14 days

开始日期2021-01-06

申办/合作机构

Starpharma Pty Ltd.

EUCTR2019-004332-36-GB / Unknown status临床1/2期

A Phase 1/2 Modular, Multi-Arm Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of DTX-SPL8783 (DEP docetaxel/DEP-DTX) in Combination with Anti-Cancer Treatments, in Patients with Advanced Malignancies - Study of DTX-SPL8783 in Combination with Anti-Cancer Treatments

开始日期2020-02-01

申办/合作机构

Starpharma Pty Ltd.

EUCTR2019-001318-40-GB / Unknown status临床1/2期

A phase 1/2 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of SN38-SPL9111 (DEP®-SN38), a SN38 dendrimer conjugate, in patients with advanced solid tumours. - SN38-SPL9111 in advanced solid tumours

开始日期2019-08-07

申办/合作机构

Starpharma Pty Ltd.

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项与 Starpharma Pty Ltd. 相关的文献（医药）

2024-06-01·Journal of Clinical Oncology

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (DEP CTX) in patients with advanced solid cancers in a phase 1/2 trial (P1/2).

作者: Aboud, Karam ; Korolewicz, James ; Le Meur, Julia ; Pinato, David James ; Edmondson, Stephanie Ruth ; Liu, Jia (Jenny) ; Jones, Robert Hugh ; Cosman, Rasha ; Morton, Cienne ; Paull, Jeremy ; Forster, Martin ; Joshua, Anthony M. ; Main, Nicola Jane ; Spicer, James F.

3004 Background: DEP CTX is a highly optimized dendrimer nanoparticle formulation of cabazitaxel that achieves sustained cytotoxic drug delivery to tumors via enhanced permeability & retention effects. Unlike standard cabazitaxel (s-CTX), DEP CTX is highly water soluble, does not contain toxic excipients associated with anaphylaxis & does not require steroid/antihistamine premedication. We report the final P2 efficacy and safety results in patients (pts) with advanced/metastatic solid tumors. Methods: Pts were treated with DEP CTX at 20 mg/m2 cabazitaxel, IV 3-weekly. Efficacy was assessed by RECIST v1.1, Prostate Cancer Working Group 3 (PCWG3) guidelines or serum tumor markers; evaluable pts had relevant criteria at baseline and a follow-up assessment per protocol window. Safety was assessed by CTCAE v4.03. (EudraCT 2017-003424-76). Results: In P2, 75 pts were enrolled, prioritizing metastatic castration-resistant prostate cancer (mCRPC, s-CTX’s only approved indication), esophagogastric (EG) & ovarian (OV) cancers. For all pts, median progression free survival (mPFS) and overall survival (mOS) were 3.8 and 9.0 mths, respectively. Objective response rate (ORR) was 20% in 45 evaluable pts. All 25mCRPC pts were heavily pre-treated with a median of 4 prior lines of anticancer treatment. mPFS was 4.4 mths (radiographic or prostate specific antigen [PSA]); mOS was 14.7 mths. The disease control rate (DCR) was 70.6%; ORR was 16.7%. PSA reduced in 90% pts (by > 50% in 52.4%); 87% with bone metastases had no progression or improved. Of 15 EG pts, 9 were adenocarcinoma (ADENO) (3 gastric, 2 esophageal & 4 EG junction) & 6 were esophageal squamous cell carcinoma (SCC). For all EG pts, mPFS was 4.0 mths, mOS was 8.6 mths. mPFS was 4.0/1.9 mths for ADENO/SCC, respectively. Overall, DCR was 80%; ORR 30%. DCR was 100%/50% and the ORR was 33%/25% for ADENO/SCC, respectively. Of 22 OV pts, 96% were platinum resistant (Pt-R), with a median of 4 prior lines of anticancer treatment, including 59% with ≥ 3 platinum lines. mPFS/mOS were 3.1 mths & not reached, respectively. DCR was 66.7%; ORR 17.6%. Treatment related adverse events (TRAEs) were mostly mild/moderate (grade (G) 1/2; 64%/25%). Only 21% of pts had G 3/4 non-hematological TRAEs, while G3/4 lab detected neutropenia was seen in only 23% of pts despite no routine G-CSF. TRAEs observed in ≥10% of pts included fatigue, neutropenia, anemia, thrombocytopenia, diarrhea, nausea, vomiting, peripheral neuropathy and decreased appetite. Conclusions: DEP CTX exhibited clinically meaningful, durable antitumor activity in multiple advanced solid cancers, including mCRPC, Pt-R OV and EG cancers without the need for steroid premedication. The antitumor activity & safety results compare favorably to s-CTX, or standard of care chemotherapy in non-prostate cancers, and highlight the promising potential of dendrimer-enhanced delivery of cabazitaxel. Clinical trial information: 2017-003424-76 .

2024-01-20·Journal of Clinical Oncology

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (CTX-SPL9111) in advanced esophagogastric cancers in a phase 1/2 trial.

作者: Aboud, Karam ; Pinato, David James ; Korolewicz, James ; Cosman, Rasha ; Forster, Martin D. ; Spicer, James F. ; Benafif, Sarah ; Joshua, Anthony M. ; Liu, Jia (Jenny) ; Fairley, Jacinth ; Edmondson, Stephanie Ruth ; Paull, Jeremy ; Jones, Robert Hugh

374 Background: There is a significant unmet need in esophagogastric cancers (EGC) due to limited effective treatments (Tx) and poor prognosis. Dendrimers are highly branched nanoparticles that enable sustained delivery of cytotoxic drugs and achieve selective tumor targeting via an enhanced permeability and retention effect. DEP cabazitaxel is a highly optimised dendrimer formulation of cabazitaxel. Unlike standard cabazitaxel, DEP cabazitaxel is highly water soluble, does not contain toxic excipients such as polysorbate-80 associated with anaphylaxis, and avoids the need for steroid/antihistamine pre-medication. The objective of this Phase 1/2 trial was to assess preliminary efficacy and safety of DEP cabazitaxel in patients (pts) with advanced solid tumors including EGC, for which standard cabazitaxel is not approved. Methods: In the P2 part of the trial, advanced EGC pts with measurable disease were treated with DEP cabazitaxel 20 mg/m2 cabazitaxel, the recommended Phase 2 dose, IV 3-weekly. Anti-tumour activity was assessed by RECIST v1.1, safety by CTCAE v4.03. (EudraCT 2017-003424-76). Results: Fifteen pts with advanced EGC were enrolled; 9 adenocarcinoma (ADENOCA) (3 gastric, 2 esophageal and 4 EG junction) and 6 esophageal squamous cell carcinoma (ESCC); median age 62 yrs (26–73 yrs), with all pts having ≤3 prior anticancer Tx, and the majority (9) having progressed on or immediately after 1st line Tx (1L). All had ≥1 prior platinum-based regimen and 4 pts had received prior taxanes. Pts received a median of 4.5 DEP cabazitaxel cycles without the need for routine steroid/antihistamine or primary G-CSF prophylaxis. In all evaluable pts, disease control rate (DCR) was 80%. Disease control was observed in both histological subtypes and was durable, including stable disease (SD) for up to 27 weeks and partial responses (PR) for up to 17 weeks, with objective response rate (ORR) of 30%. In EG ADENOCA pts, DCR was 100%, ORR was 33%, and median progression free survival (mPFS) was 4.0 months. In ESCC pts, DCR was 50% and ORR was 25%, with mPFS of 1.9 months. DEP cabazitaxel was well-tolerated with mostly mild (62.9%, Grade (G) 1)/moderate (20.2%, G2) treatment-related adverse events (TRAEs), including nausea, vomiting, fatigue, neuropathy, neutropenia (only 1 pt had G-CSF Tx, 1 pt had secondary G-CSF prophylaxis) and anemia, that were like those observed with standard cabazitaxel Tx. Of severe TRAEs (G3/4; 16.9%) most (80%) were observed in 2 pts, including neutropenia, anemia, thrombocytopenia, fistula, elevated liver enzymes. Conclusions: DEP cabazitaxel exhibited highly encouraging anti-tumor activity in >1L, advanced EGC in multiple anatomic locations and of different histological sub-types. The preliminary efficacy and safety results compare favorably to available treatment options and highlight the promising clinical potential of DEP cabazitaxel in advanced EGC. Clinical trial information: EudraCT 2017-003424-76 .

2023-12-01·Molecular Cancer Therapeutics

Abstract B039: A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111/DEP irinotecan) in patients with advanced solid tumours

作者: Yau, Wing ; Gaus, Aisha ; Edmondson, Stephanie R ; Cosman, Rasha ; Cook, Natalie ; Main, Nicola J ; Joshua, Anthony M ; Greystoke, Alastair ; Morton, Cienne ; Liu, Jia ; Jean-Francois, Bernadette M ; Evans, Thomas R J ; Fairley, Jacinth K ; Paull, Jeremy R A ; Sarker, Debashis ; Chwialkowska, Dominika ; Minchom, Anna R

AbstractBackground: Dendrimers are highly branched nanoparticles that achieve significant tumor targeting of cytotoxic drugs. DEP SN38 (or DEP irinotecan) is a highly optimised dendrimer conjugate of the irinotecan active metabolite, SN38. We report initial results of a phase 1/2 trial evaluating the safety, tolerability and preliminary efficacy of DEP SN38 in patients (pts) with advanced solid tumors, including colorectal (CRC) and platinum-resistant high-grade serous ovarian carcinoma (HGSOC).Methods: Solid tumor pts who had exhausted standard therapy were enrolled (EudraCT2019-001318-40). DEP SN38 given IV 3-weekly (Q3W) was escalated to identify a recommended phase 2 dose (RP2D). Additional dose assessment/expansion cohorts followed at Q3W or Q2W (2-weekly) alone or in combination with 5-fluorouracil and leucovorin (5FU/LV). Efficacy was assessed via RECIST 1.1 criteria and serum tumor biomarkers.Results: Dose escalation (N=7) confirmed a Q3W RP2D of 12.5 mg/m2 SN38 with 1 pt having a dose limiting toxicity (DLT) of grade 4 neutropenia for >7d. Following successful dose expansion, additional dose exploration confirmed a Q2W RP2D of 12.5 mg/m2 SN38 alone or in combination with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens (N=101) with mostly mild/moderate treatment-related adverse events (TRAEs), with no new events compared to those observed with conventional irinotecan. Notably, there were no reports of severe (≥ grade 3) diarrhea with DEP SN38 and no reports of cholinergic symptoms, both being common with conventional irinotecan (~20% and 47% pts, respectively). Moreover, with DEP SN38, severe nausea (2.2% pts) and vomiting (1.1% pts) occurred less frequently than with irinotecan (both ~10% pts). While febrile neutropenia was observed as a DLT at 15 mg/m2 Q2W monotherapy (2 pts), neutropenia was otherwise uneventful and managed with G-CSF.CRC pts: 38 heavily pre-treated CRC pts were dosed (N=31 evaluable); pts had an average ~4 prior treatment lines with 97% having received at least 1 irinotecan containing line. DEP SN38 achieved a disease control rate (DCR) of 48%, with stable disease up to 72 weeks.HGSOC pts: 23 platinum-resistant HGSOC pts were dosed (N=18 evaluable); pts had received an average ~6 prior treatment lines. DCR for pts dosed Q2W was 100% with 33.3% objective response rate, and 72% DCR for all HGSOC pts. There were 3 partial responses (PR), for up to 27 wks with 1 pt achieving complete tumour and ascites resolution with pts ongoing. 75% of pts achieved CA-125 reductions of up to 98% vs baseline. For DEP SN38 in combination with 5FU/LV, in a cohort of mainly CRC pts (N=6), DCR is 100% including 1 PR, with pts ongoing.Conclusions: DEP SN38 was very well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to conventional irinotecan. Encouraging anti-tumour activity, including prolonged disease control in heavily pre-treated CRC and HGSOC pts, demonstrates promising clinical utility of DEP SN38, both as a monotherapy and as a combination therapy. Recruitment is ongoing.Citation Format: Jia Liu, Anna R Minchom, Alastair Greystoke, Thomas R J Evans, Debashis Sarker, Anthony M Joshua, Cienne Morton, Aisha Gaus, Wing Yau, Rasha Cosman, Dominika Chwialkowska, Jeremy R A Paull, Bernadette M Jean-Francois, Jacinth K Fairley, Nicola J Main, Stephanie R Edmondson, Natalie Cook. A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111/DEP irinotecan) in patients with advanced solid tumours [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B039.

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