Taxane

卵巢癌是全球第二大常见妇科恶性肿瘤，约80%–85%的患者可能会面临复发风险。几乎所有患者最终都会发展为铂类耐药性疾病，约25%的患者在首次复发时表现出耐药性。紫杉醇治疗仍然是此类患者治疗的基石之一。多种其他治疗方式单独使用或与紫杉醇联合使用会产生类似或增加的毒性，并且无法延长生存期。因此，迫切需要新的治疗方法。 近期，《妇科肿瘤学》报道了“ 电场疗法（TTFields）治疗卵巢癌，2期INNOVATE（EF-22）研究（NCT02244502）的惊艳数据 ”！ 一、肿瘤电场治疗联合紫杉醇暴击复发性卵巢癌，中位总生存（OS）率达90% 本次研究共入组31例患者，参加试验的所有患者均经组织学证实患有复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌，中位年龄为60岁（范围：45-77岁），且接受过多种先前疗法。评估结果显示患者的预期寿命至少为12周，且东部肿瘤协作组(ECOG)评分为0-1。其中，大多数患者(77%)具有浆液性组织学和III期疾病（根据美国癌症联合委员会卵巢癌TNM分期），既往化疗线数中位数为4（范围：1-11）。所有患者均接受过铂类化疗，30名患者（97%）接受过紫杉烷类化疗。患者入组后，接受NovoTTF-100L(O)电场治疗，这是一种便携式医疗设备，使用4个换能器阵列向骨盆/腹部传送交变电场，该系统使用电池供电时可随身携带，允许患者进行正常的日常活动。中位随访时间为8.9个月（范围：1.7-20.4）。 ▲图源“Gynecologic oncology”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 结果显示： 中位无进展生存期（PFS）为8.9个月（95%CI 4.3-未达到） （详见下图）。 25%的患者报告有部分缓解，另外46%的患者病情稳定。从部分缓解或病情稳定到肿瘤进展的中位持续时间为6.5个月。 尽管在进展时停止了TTFields，但值得注意的是， 与病情进展的患者相比，病情部分或稳定的患者的TTFields治疗周期中位数在统计学上明显更高（分别为5个月和2个月，p =0.0002） 。 ▲图源“Gynecologic oncology”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 此外， 6个月的中位总生存（OS）率高达90%，1年的中位总生存（OS）率为61% （详见下图）。 ▲图源“Gynecologic oncology”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 综上，电场疗法（TTFields）联合每周紫杉醇治疗铂耐药复发性卵巢癌是安全的，为此类患者带来了一线生机，而且鉴于电场疗法随身携带的特性，免去了患者频繁往返医院的苦恼。 二、抗癌黑科技登场：能随时佩戴的肿瘤电场疗法 电场疗法（TTFields）是一种新型的非侵入性局部区域性抗有丝分裂治疗方法，通过覆盖在皮肤上的电极阵列，向肿瘤部位施加低强度（1~3 V/cm）、中频（100~300 kHz）交变电场，最终达到抑制癌细胞扩散和转移的目的。 电场疗法（TTFields）已获得美国FDA 批准用于治疗胶质母细胞瘤，并在欧洲获得了相同适应症的 CE 标志：与替莫唑胺维持治疗相结合时，TTFields 将新诊断的胶质母细胞瘤患者的中位 OS 延长了约 5 个月（风险比为 0.63；p = 0.00006），并将 5 年生存率从 5% 提高到 13%，且不会增加全身毒性。由于 TTFields 作用于所有真核细胞共有的有丝分裂过程阶段，因此它们有可能靶向其他癌症。事实上，TTFields 已被证明在 胰腺癌、非小细胞肺癌、间皮瘤和其他类型肿瘤 的体外和体内模型中有效。 更为值得一提的是，电场疗法（TTFields）具有使用方便的独特优势，可在家中佩戴使用并完成治疗，避免了癌症患者频繁跑医院的困扰，不影响患者的日常生活。此外，由于 TTFields 选择性地针对癌细胞的不同特性，例如分裂速度和形态，因此健康细胞基本上不受影响。 三、中国如何开展电场疗法？ 目前中国患者可通过以下三种方式，寻求电场疗法的帮助： 1、 在医院接受正规治疗 ：电场疗法目前已在美国、日本、中国等多个国家获批上市，国内患者现可前往指定医院进行正规治疗（但国内电场疗法目前价格较高，具体可咨询医学部）。 2、 参加临床试验 ：电场疗法虽已获批上市，但在全球范围内，仍属于前瞻性治疗，目前国内和国外都开展了大量的临床试验，患者可通过 全球肿瘤医生网医学部 ，了解详细的入排标准。 3、 寻求日本ECCT疗法帮助 ：日本电场疗法被称为ECCT，是依据电场原理研发的，与美国TTF电场疗法相比，暂时缺少大型的临床试验数据。但相较于昂贵的TTF，日本ECCT设备的费用相对较低（约9万人民币/套），穿戴时间是TTF治疗的1/3左右，国内患者可购买回国内长期使用。 四、小编寄语 肿瘤电场疗法作为一种可居家使用的无创的物理疗法，在治疗恶性肿瘤方面具有独特的优势，可随身佩戴，实现随时随地抗癌的效果，可用于治疗肺癌、脑胶质母细胞瘤、胃癌、胰腺癌等多款肿瘤，以达到预防肿瘤复发或转移、延长患者生存期的目的。 五、参考资料 [1]Vergote I,et al.Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study[J]. Gynecologic oncology, 2018, 150(3): 471-477. https://www.gynecologiconcology-online.net/article/S0090-8258(18)31082-5/fulltext 本文为全球肿瘤医生网原创，未经授权禁止转载。

HIGHLIGHTS Safety Review Committee (SRC) meeting confirms end of the Dose Escalation Phase and commencement of the Cohort Expansion Phase (Phase II stage) of the SECuRE study. Based on the efficacy and safety assessment of all cohorts and the focus on earlier stages of treatment, the SRC confirmed expansion at 8 GBq dose level and recommended to increase the number of cycles from up to 4 to up to 6. Cohort 4 of the Dose Escalation Phase of the SECuRE trial, assessing multiple administrations of 67Cu-SAR-bisPSMA, is complete. Prostate-specific antigen (PSA) levels are continuing to drop in 3 participants, with reductions ≥80% observed in 3 cases so far. A complete response was achieved in a participant in cohort 4 following 2 doses of 12 GBq of 67Cu-SAR-bisPSMA to date, based on the Response Evaluation Criteria in Solid Tumors v1.1 (RECIST). Across all cohorts, 68% of participants have shown reductions in PSA levels, despite the vast majority of the participants (77%) only receiving a single dose of 67Cu-SAR-bisPSMA. The majority of participants that did not respond to the treatment had received chemotherapy in the metastatic castration-resistant prostate cancer (mCRPC) stage, were part of the lowest dose cohort (cohort 1) and had some of the highest PSA levels at study entry. 67Cu-SAR-bisPSMA has shown a favourable safety profile across all cohorts. The majority of reported adverse events (AEs) were Grade 1-2, with anaemia and thrombocytopenia being the most prevalent among the haematological events. Most AEs have now resolved. One Dose Limiting Toxicity (DLT) in 1 participant occurred at the highest dose in cohort 4, a transient Grade 4 thrombocytopenia, which improved to Grade 3 after 2 weeks. This participant had bone metastases, a high baseline PSA [1503.12 ng/mL] and had previously been treated with chemotherapy and multiple lines of 177Lu-PSMA-617. A PSA drop of 10.7% was observed following the administration of 1 cycle of 67Cu-SAR-bisPSMA. In the group of 13 participants who had not received chemotherapy in the mCRPC setting, all but 1 participant had PSA drops of 35% or more, predominantly with single doses of 67Cu-SAR-bisPSMA. PSA reductions of 80% or more were achieved in almost half of these patients. The majority of participants had received ≥3 lines of therapy prior to enrollment in the study (63.6%). Disease control based on radiographic assessment (RECIST) was achieved in 11 of the 12 (92%) pre-chemotherapy participants who had evaluable disease at baseline. The SECuRE trial protocol has been amended to bring 67Cu-SAR-bisPSMA to participants at earlier stages of their disease, in the pre-chemotherapy setting. The amendment incorporates an increase in the number of participants in the Cohort Expansion Phase of the trial from 14 to 24, with a subset of participants planned to receive the combination of 67Cu-SAR-bisPSMA with enzalutamide, an ARPi. SYDNEY, March 5, 2025 /PRNewswire/ -- Clarity Pharmaceuticals (ASX: CU6) ("Clarity" or "Company"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, is pleased to announce the completion of the Dose Escalation Phase of the SECuRE trial (NCT04868604)[1]. The SRC recommended the trial progress to the Cohort Expansion Phase (Phase II) at the 8 GBq of 67Cu-SAR-bisPSMA dose level based on the safety and efficacy data demonstrated in every cohort of the study. Across cohorts 1-4 of the SECuRE study, 68% of participants have shown reductions in PSA levels, despite the vast majority of the participants (77%) only receiving a single dose of 67Cu-SAR-bisPSMA. Most of these participants had a high level of bone metastases at study entry (77.3%), a high median PSA of 112.86 ng/mL (range 0.1-1503.1) and were heavily pre-treated with ≥3 lines of therapy (63.6%). Disease control based on radiographic assessment (complete response + partial response + stable disease) was achieved in 78% of the participants so far (including 2 partial responses and 1 complete response observed to date based on the RECIST assessment). The complete response was seen in a patient dosed twice at 12 GBq. This is the second complete response recorded following 67Cu-SAR-bisPSMA treatment, first being the patient previously reported to have a complete response following 2 doses at 8 GBq (first dose administered through the SECuRE trial, and a second dose administered under the the United States [US] Food and Drug Administration [FDA] Expanded Access Program [EAP]). Safety profile of 67Cu-SAR-bisPSMA is favourable across cohorts 1-4 with the majority of AEs being Grade 1-2. Anaemia and thrombocytopenia were the most prevalent AEs among the haematological events. No overall trends in other haematological parameters or renal safety were observed in any of the cohorts. Only 1 DLT has been reported in the trial (transient Grade 4 thrombocytopenia, which improved to Grade 3 after 2 weeks) in a patient in the highest dose cohort (cohort 4). This participant had a baseline PSA of 1503.12 ng/mL, had been treated with multiple lines of therapy, including chemotherapy in the mCRPC setting and multiple doses of 177Lu-PSMA-617, and had bone metastases prior to entering the study. The participant's baseline characteristics may have contributed to the lowering of the platelet levels. Despite the unfavourable prognosis of this participant, which included a very high PSA and being heavily pre-treated, 1 cycle of 67Cu-SAR-bisPSMA was still able to reduce his PSA by 10.7% (to 1341.80 ng/mL). Pre-chemotherapy participants Thirteen participants across cohorts 1-4 in the SECuRE trial were naïve to taxanes in the mCRPC setting (pre-chemotherapy), including 2 in cohort 1 and 3 in cohort 2. The majority of pre-chemotherapy participants had bone metastases (69.2%) with a median PSA of 42.41 ng/mL (range 0.1-182.4) at study entry. Almost half of these participants received ≥3 lines of therapy prior to trial enrolment (46.2%). Despite the heavy disease burden and the majority of participants only receiving single doses of 67Cu-SAR-bisPSMA, there was an outstanding result observed in the pre-chemotherapy setting. Out of the total of 13 pre-chemotherapy participants across all cohorts, 12 had PSA drops greater than 35%. PSA reductions greater than 50% were reached in 61.5% (8/13) of participants, and reductions of 80% or more were achieved in 46.2% (6/13) of participants. Disease control based on the RECIST assessment was also observed in 11 out of 12 pre-chemotherapy participants (92%) who had measurable disease at baseline. One participant reached a complete response with 2 doses of 12 GBq in cohort 4, 2 participants had partial responses (cohort 2 and cohort 4), and 8 participants achieved stable disease at this time. Three participants in the pre-chemotherapy setting of the SECuRE trial had previously been treated with actinium-225 based radioligand therapies (RLT) and, in 1 case, in combination with lutetium-177 based therapy. All 3 participants showed reductions in PSA levels following treatment with 67Cu-SAR-bisPSMA in the trial. Notably, 1 of these 3 participants showed a PSA reduction of 83.4% following the administration of 2 doses of 12 GBq of 67Cu-SAR-bisPSMA in cohort 4, despite being heavily pre-treated. The lines of therapy administered to the patient prior to the SECuRE trial enrollment included androgen deprivation therapy (ADT), 2 androgen receptor pathway inhibitors (ARPIs), autologous cellular immunotherapy, and investigational agents (immunotherapy and 177Lu-PSMA-I&T plus 225Ac-J591). Safety assessment in pre-chemotherapy participants was comparable to the overall patient population with most AEs being Grade 1 and Grade 2. Cohort Expansion Phase Based on the data from cohorts 1-4, the SRC recommends the SECuRE trial progress to Cohort Expansion (Phase II) at an 8 GBq dose level, with an increase in the total number of cycles from up to 4 to up to 6. This recommendation is based on the favourable safety profile of 67Cu-SAR-bisPSMA observed to date. Cohort 2 (single dose of 8 GBq of 67Cu-SAR-bisPSMA) with 3 participants had the highest rate of PSA response in the trial, and all participants in the cohort had disease control based on the RECIST assessment (including one partial response). The PSA reductions were 81.4%, 95.2% and 99.4%. Only 1 participant in this cohort developed 67Cu-SAR-bisPSMA-related AEs (Grade 1 dry mouth and altered taste, both improved, and Grade 2 fatigue, resolved). No haematological toxicity was reported in the cohort. The first patient to receive 2 doses of 67Cu-SAR-bisPSMA at 8 GBq (first dose through the SECuRE trial and second dose under the US EAP) achieved a complete anatomical, molecular and biochemical response (assessed by the RECIST criteria, positron emission tomography [PET] and PSA, respectively). He had been heavily pre-treated (chemotherapy in the neoadjuvant setting, ADT, 2 ARPIs and an investigational agent) prior to entering the SECuRE study. The patient's recent follow up showed that he remains with undetectable PSA for almost 16 months, having received his first dose of 67Cu-SAR-bisPSMA over 20 months ago (June 2023). A recent PSMA PET showed no signs of recurrent or metastatic disease. Most AEs related to 67Cu-SAR-bisPSMA were mild or moderate, with the majority having either improved or resolved over time. Based on these safety and efficacy data, where exceptional efficacy signals were observed at lower radiation doses, 8 GBq was chosen as an optimal dose for the Cohort Expansion Phase. The SECuRE trial protocol has been amended to include evaluation of mCRPC participants who have not received chemotherapy in the metastatic (pre-chemotherapy) setting. This amendment is aligned with Clarity's strategy of bringing 67Cu-SAR-bisPSMA to participants with earlier stages of the disease and is based on the promising safety and efficacy data, especially in pre-chemotherapy participants of the SECuRE trial. The protocol amendment also incorporates an increase in the number of participants in the Cohort Expansion Phase of the trial from 14 to 24, in which a subset of participants will receive the combination of 67Cu-SAR-bisPSMA with enzalutamide, an ARPI. These changes are aimed at optimising the development of all of Clarity's products in prostate cancer, following ongoing discussions with and advice from many important global medical experts in the field of prostate cancer, including the Company's Clinical Advisory Board members, Prof Louise Emmett and Prof Oliver Sartor, as well as the SRC. Clarity's Executive Chairperson, Dr Alan Taylor, commented, "The SECuRE trial continues to generate extraordinary results, and we thank our team, Principal Investigators, members of the SRC, and especially the participants who have contributed to the study. Seeing the safety profile and already observing impressive signs of efficacy (despite the majority of participants only receiving a single cycle of 67Cu-SAR-bisPSMA and the primary focus of the Dose Escalation Phase being safety assessments), we are thrilled to progress to Phase II, the Cohort Expansion Phase, of our theranostic SECuRE trial. "Dose escalation trial design has not been routinely used in other RLT studies. By pioneering this approach with the SECuRE trial, Clarity was looking to systematically evaluate the safety of 67Cu-SAR-bisPSMA in the context of its therapeutic effect. By gradually increasing the dose from one cohort to the next, we have minimised the risk of AEs and established a favourable safety profile for patients, while also demonstrating that 67Cu-SAR-bisPSMA is effective. "We are looking forward to executing our strategy of bringing 67Cu-SAR-bisPSMA to earlier lines of prostate cancer therapy with the recent protocol amendment, given the exciting data in pre-chemotherapy participants. We are also increasing the number of participants in the Cohort Expansion Phase. This decision is partly motivated by the increased demand from oncologists to include their participants into the trial, but it is also led by our decision to explore potential benefits of using a combination of 67Cu-SAR-bisPSMA with enzalutamide, following consultation with world-leading prostate cancer oncologists and nuclear medicine physicians. "With our focus on treating earlier stage disease (pre-chemotherapy in the mCRPC setting), it is an incredible outcome to have 12 out of 13 pre-chemotherapy participants in the trial experiencing greater than 35% reductions in PSA and almost half of the 13 experiencing drops of 80% or greater. PSA reductions were seen across all cohorts, including the lowest 4 GBq cohort where all pre-chemotherapy participants exhibited greater than 50% drops in PSA from a single dose. Remarkably, one of those participants has had 4 additional doses under EAP and achieved disease control for over 2 years since first treatment. The results from 3 pre-chemotherapy participants who received 8 GBq of 67Cu-SAR-bisPSMA have been outstanding with a favourable safety profile and excellent efficacy, where PSA reductions were greater than 80% for all participants and above 95% for 2 out of the 3 participants, with all of them achieving radiographic disease control and 1 showing a complete response to date. "The very compelling safety and efficacy data for SAR-bisPSMA that we continue generating stems from Clarity's strong adherence to the highest level of scientific and clinical research. At the heart of this rigorous approach is the dimer "bis" molecule developed at the benchtop of Australian science and translated into the clinic. When optimising the PSMA molecule, the goal was to create an ideal candidate for both therapy and diagnosis of prostate cancer. We wanted to overcome the shortfalls of the current generation of PSMA-targeting products, increasing not only the amount of product in the lesions, but also how long the product is retained in the lesions over time. We are now seeing these results in the clinic with 67Cu-SAR-bisPSMA in the SECuRE trial and with 64Cu-SAR-bisPSMA in our diagnostic trials. "The recent receipt of 3 Fast Track Designations from the US FDA for our optimised SAR-bisPSMA molecule, one of which was based off the data presented here, is testament to the high quality of this data, but also reflects a critical need for novel solutions in prostate cancer management. With an estimated combined market value of approximately US$10-15 billion by 2030 for PSMA-targeted products, we are hoping to address the evident high unmet need in this segment, from first diagnosis to the treatment of metastatic disease, and improve treatment outcomes for men with prostate cancer around the world. "We look forward to swiftly recruiting into the next phase of the SECuRE trial, moving towards a Phase III pivotal trial. We are very excited about what the future holds for this promising product and are working tirelessly to bring it to people who need it most in a timely manner, whilst adhering to the highest standards of clinical research." About the SECuRE trial The SECuRE trial (NCT04868604)[1] is a Phase I/IIa theranostic trial for identification and treatment of participants with PSMA-expressing mCRPC using 64Cu/67Cu-SAR-bisPSMA. 64Cu-SAR-bisPSMA is used to visualise PSMA-expressing lesions and select candidates for subsequent 67Cu-SAR-bisPSMA therapy. The trial is a multi-centre, single arm, dose escalation study with a cohort expansion involving approximately 54 participants in the US and Australia. The overall aim of the trial is to determine the safety and efficacy of 67Cu-SAR-bisPSMA for the treatment of prostate cancer. About SAR-bisPSMA SAR-bisPSMA derives its name from the word "bis", which reflects a novel approach of connecting two PSMA-targeting agents to Clarity's proprietary sarcophagine (SAR) technology that securely holds copper isotopes inside a cage-like structure, called a chelator. Unlike other commercially available chelators, the SAR technology prevents copper leakage into the body. SAR-bisPSMA is a Targeted Copper Theranostic (TCT) that can be used with isotopes of copper-64 (Cu-64 or 64Cu) for imaging and copper-67 (Cu-67 or 67Cu) for therapy. 67Cu-SAR-bisPSMA and 64Cu-SAR-bisPSMA are unregistered products. The safety and efficacy of 67Cu-SAR-bisPSMA and 64Cu-SAR-bisPSMA have not been assessed by health authorities such as the US FDA or the Therapeutic Goods Administration (TGA). There is no guarantee that these products will become commercially available. About Prostate Cancer Prostate cancer is the second most common cancer diagnosed in men globally and the fifth leading cause of cancer death in men worldwide[2]. Prostate cancer is the second-leading causes of cancer death in American men. The American Cancer Institute estimates in 2025 there will be about 313,780 new cases of prostate cancer in the US and around 35,770 deaths from the disease[3]. About Clarity Pharmaceuticals Clarity is a clinical stage radiopharmaceutical company focused on the treatment of serious diseases. The Company is a leader in innovative radiopharmaceuticals, developing Targeted Copper Theranostics based on its SAR Technology Platform for the treatment of cancers in children and adults. For more information, please contact: References ClinicalTrials.gov Identifier: NCT04868604, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, American Cancer Society: Key Statistics for Prostate Cancer, This announcement has been authorised for release by the Executive Chairperson. SOURCE Clarity Pharmaceuticals WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED