On September 13, 2023 Starpharma (ASX: SPL, OTCQX: SPHRY) reported that positive interim results from its Phase 1/2 clinical trial of DEP irinotecan will be presented at the upcoming American Association of Cancer Research (AACR) (Free AACR Whitepaper), National Cancer Institute (NCI) and European Organisation for Research and Treatment of Cancer (EORTC) AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston, US, from 11 to 15 October 2023 (Press release, Starpharma, SEP 13, 2023, View Source;mc_eid=bf52dd3418 [SID1234635114]).
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DEP irinotecan is a novel, patented, nanoparticle formulation of SN38, the active metabolite of the widely used anti-cancer drug, irinotecan (marketed as Camptosar), developed using Starpharma’s proprietary DEP technology.
The DEP irinotecan data being presented include encouraging durable signs of efficacy combined with excellent tolerability not only in the irinotecan-approved indication of advanced metastatic colorectal cancer (CRC), but also in platinum-resistant/refractory ovarian cancer, which represents a new market opportunity. These positive results, including prolonged disease control and significant tumour shrinkage, have been achieved in heavily pre-treated patients who have received an average of up to 6 prior treatment regimens and 31 cycles and exhausted all available treatment options.
The data will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) by Dr Jenny Liu, MD, PhD, FRACP, Medical Oncologist and Principal Investigator at the Kinghorn Cancer Centre, St Vincent’s Hospital in Sydney, who commented on the positive results:
"The results of the DEP irinotecan trial to date have been very promising for patients with advanced colorectal cancer who have exhausted standard treatment options, with prolonged responses and excellent tolerance of the product, including in patients who could not previously tolerate standard irinotecan or had failed prior therapy.
"Our experience in treating more than 20 patients on the trial to date have shown promisingly low rates of severe gastrointestinal adverse events and absence of cholinergic toxicity, which are both common and problematic side effects of standard irinotecan therapy. I am also getting consistent feedback from several patients in the trial that they far prefer DEP irinotecan plus 5-FU/LV compared to the standard FOLFIRI regimen, which uses conventional irinotecan.
"In this heavily pre-treated group of CRC patients, prolonged disease control seen with DEP irinotecan is an excellent outcome and a significant clinical benefit and warrants ongoing development."
Dr Natalie Cook, MBChB, MRCP, PhD, the Principal Investigator of the study, a Medical Oncologist and Clinical Lead for the Manchester Experimental Cancer Medicine Centre at the Christie Hospital and University of Manchester in the UK, commented:
"I am impressed with the data on Starpharma’s novel dendrimer formulation of the irinotecan active metabolite, SN38. In our patients, DEP irinotecan has shown excellent tolerability and very encouraging efficacy.
"Compared to conventional irinotecan, tolerability for DEP irinotecan is much improved. Based on the trial data, I believe DEP irinotecan represents a well-tolerated and promising treatment alternative for patients with colorectal cancer, and potentially others, including platinum-resistant ovarian cancer."
DEP irinotecan interim clinical results in colorectal cancer1 (CRC)
Advanced metastatic CRC patients enrolled in the monotherapy cohort (N=38) were heavily pre-treated, having received an average of 4 prior treatment regimens and 31 cycles before entering the study. These patients, aged 35 to 78 years, had exhausted all available treatment options. All but one (97%) of the patients had progressed after prior treatment with conventional irinotecan (up to 4 lines) either as monotherapy or in combination. Despite this heavy pre-treatment, DEP irinotecan monotherapy achieved durable efficacy responses (stable disease [SD] and tumour shrinkage) for up to 72 weeks (~16 months), with disease control in 48% (15/31) of evaluable2 patients.
DEP irinotecan is also being evaluated in combination with 5-fluorouracil (5-FU) and leucovorin (LV), which is a standard irinotecan combination regimen used in the treatment of CRC known as "FOLFIRI". In this combination cohort, there are five evaluable CRC patients thus far, with treatment and enrolment ongoing. The DCR3 achieved in this cohort is 100%, with an ORR4 of 20%. For comparison, published data in advanced CRC patients for conventional irinotecan plus 5-FU/LV (FOLFIRI) as second-line therapy (i.e., in patients less heavily pre-treated than in the current study) reported an ORR of 4%5. In the DEP irinotecan combination cohort, clinicians have reported significant clinical benefit in these heavily pre-treated patients, including durable responses for up to 27 weeks (SD and partial response [PR]) and very good tolerability. Multiple patients have also provided positive feedback about the improved quality of life experienced with DEP irinotecan compared to conventional irinotecan therapy.
DEP irinotecan interim clinical results in platinum-resistant/refractory ovarian cancer
In addition to the positive results in CRC patients, DEP irinotecan demonstrated excellent responses in patients with advanced metastatic ovarian cancer (N=23). These patients were very heavily pre-treated, with an average of ~6 prior treatment regimens and 30 cycles before treatment with DEP irinotecan. Furthermore, all patients’ cancer was resistant or refractory to platinum-based therapies, which are the standard-of-care in ovarian cancer, and patients had exhausted all available standard-of-care treatment options.
DEP irinotecan monotherapy achieved a DCR of 100% and an ORR of 29% in ovarian cancer patients dosed every 2 weeks (Q2W). The DCR achieved in all ovarian cancer patients (Q2W and Q3W) is 72%, with several patients continuing to receive treatment and experiencing clinical benefit.
DEP Irinotecan Response Rates in Platinum-Resistant/Refractory Ovarian Cancer Patients
Endpoint
DEP Irinotecan Dosing Regimen
Once every 2 weeks (Q2W)
(N=7)
Q2W + Once every 3 weeks (Q3W)
(N=18)
DCR
100%
72.2%
ORR
28.6%
16.7%
DCR, disease control rate; ORR, objective response rate
Responses to DEP irinotecan treatment in these heavily pre-treated ovarian cancer patients have included tumour shrinkage of up to 60%, response durations of up to 36 weeks, and tumour biomarker reductions of up to 98% in more than 75% of patients. Clinical benefits reported by investigators in the study included complete resolution of a patient’s debilitating tumour-related ascites and pleural effusion.
DEP irinotecan’s impressive ORR of 29% in these heavily pre-treated patients compares favourably to standard-of-care single-agent therapies for platinum-resistant ovarian cancer, including paclitaxel (Taxol), topotecan (Hycamtin), gemcitabine (Gemzar) or pegylated liposomal doxorubicin (Caelyx), which report ORRs ranging from ~9 to 16%6,7,8.
This cohort of patients with platinum-resistant/refractory ovarian cancer represents a significant unmet medical need and a potential expansion of the current market for irinotecan, given conventional irinotecan is not approved for the treatment of ovarian cancer, either alone or in combination.
The anti-tumour activity of DEP irinotecan, including prolonged disease control in heavily pre-treated CRC and ovarian cancer patients, is encouraging as it demonstrates the promising clinical utility of DEP irinotecan and its potential for application in colorectal and platinum-resistant/refractory ovarian cancers.
In addition to CRC and ovarian cancer, DEP irinotecan has also shown encouraging efficacy signals in pancreatic, gastrointestinal and breast cancer patients.
Safety and tolerability of DEP irinotecan
Throughout the study, DEP irinotecan therapy has been very well tolerated, with significantly fewer severe gastrointestinal treatment-related adverse events (TRAEs) reported compared to published data on conventional irinotecan.
Importantly, DEP irinotecan therapy resulted in no reports of severe or life-threatening (≥ grade 3) diarrhoea across ~100 patients enrolled in the study. This result is a significant improvement in the side effect profile when compared to conventional irinotecan (Camptosar) treatment, which is associated with severe or life-threatening diarrhoea in more than 20% of patients9. Irinotecan-induced diarrhoea is frequently associated with the discontinuation of treatment and hospitalisation, and can have potentially fatal outcomes.
In patients treated with DEP irinotecan, either alone or in combination with 5-FU/LV, there have also been no reports of cholinergic syndrome, which occurs in approximately 47% of patients treated with conventional irinotecan8. This problematic adverse event involves symptoms such as acute diarrhoea, slow heartbeat, low blood pressure, increased salivation and tears, blurred vision, excessive sweating, flushing, and abdominal cramping.
TRAEs for DEP irinotecan have been mostly mild/moderate and include nausea, vomiting, fatigue, hair loss, and bone marrow toxicity (myelosuppression). Importantly, there have also been no immune-mediated adverse events with DEP irinotecan, making it suitable for combination with immune-oncology agents. In addition, no new adverse events were observed with DEP irinotecan compared to conventional irinotecan.
Gastrointestinal Treatment-Related Adverse Events (TRAE) in CRC Patients Treated with DEP Irinotecan Monotherapy* versus Camptosar^ (Conventional Irinotecan)
Treatment
DEP Irinotecan
Camptosar
DEP Irinotecan
Camptosar
TRAE
Grade 3/4
Grade 3/4
All Grades
All Grades
Diarrhea
0%
22%
33.3%
84%
Nausea
2.6%
12.7%
71.8%
70%
Vomiting
0%
14%
30.8%
62%
*N=38; ^N=316
Dr Jackie Fairley, CEO at Starpharma, said:
"We are pleased to report positive results for DEP irinotecan, which has shown promising activity and significantly improved tolerability in advanced colorectal cancer and ovarian cancer. The conference in October is a great opportunity to showcase both DEP irinotecan and the DEP platform more broadly.
"Starpharma has received consistent feedback from patients and clinicians indicating that DEP irinotecan represents a better-tolerated treatment option than conventional irinotecan regimens, which are the mainstay chemotherapeutics for colorectal cancer. Advanced colorectal and ovarian cancers both represent significant unmet medical needs. According to the World Health Organisation (WHO), an increase of about 70% in colorectal cancers globally is expected by 2030."
Recruitment into the DEP irinotecan trial has been completed for the monotherapy arm, with a small number of ovarian cancer patients ongoing. Recruitment of colorectal cancer patients into the combination arm is approaching completion and is expected to complete during September 2023, with top-line Phase 2 results to be released following completion of patient treatment and data analyses. While finalising the enrolment, treatment and analyses of clinical trial results, Starpharma is also engaging in commercial partnership discussions for DEP irinotecan and other DEP assets.
NOTES
About DEP irinotecan
DEP irinotecan is a novel, patented, nanoparticle formulation of SN38, the active metabolite of the widely used anti-cancer drug, irinotecan (marketed as Camptosar), delivered using Starpharma’s proprietary DEP technology. Camptosar and all generic forms of conventional irinotecan carry ‘black box’ warnings mandated by the US Food and Drug Administration (FDA) for both neutropenia and severe diarrhoea, which can be dose-limiting and life-threatening. DEP irinotecan has not resulted in severe diarrhoea in Phase 2 studies. DEP irinotecan has patent filings to 2039 and up to an additional five years.
The severe diarrhoea caused by conventional irinotecan results from the production of toxic metabolites during the liver metabolism of irinotecan to SN38. DEP irinotecan was designed to eliminate the need for liver metabolism, thereby avoiding the production of toxic metabolites.
About Starpharma’s DEP irinotecan Phase 2 clinical trial
Starpharma is evaluating DEP irinotecan as both a monotherapy and in combination with 5-fluorouracil (5-FU) and leucovorin (LV), which is a standard irinotecan combination regimen used in the treatment of CRC known as "FOLFIRI". The Phase 2 DEP irinotecan trial is being conducted at multiple sites, including Guy’s Hospital in London, Beatson Cancer Centre in Glasgow, Imperial College London, and the Kinghorn Cancer Centre in Sydney.
Clinical and commercial opportunity for DEP irinotecan
The global colorectal cancer drugs market was valued at ~US$14 billion in 2023 and is forecast to reach more than US$16 billion by 202710.
Camptosar and generic forms of conventional irinotecan are standard-of-care treatments for advanced CRC, with Pfizer’s Camptosar achieving peak sales of ~US$1.1 billion. CRC accounts for approximately 10% of all new cancer diagnoses and is the second leading cause of cancer, affecting more than 1 million people annually, and is the fourth leading cause of cancer-related death.
CRC incidence is increasing markedly among younger age groups, with rates of colon cancer more than doubling in adults aged 20 to 54 since the 1990s. Studies have shown that, compared with adults born around 1950, those born around 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer11.