Inequality factors in access to early-phase clinical trials in oncology in France: results of the EGALICAN-2 study.

BACKGROUND: Investigation of the disparities in the access to experimental treatment in early-phase clinical trials is lacking. The objective of the EGALICAN-2 study was to identify the factors underpinning such inequalities. METHODS: A national prospective survey was conducted in 11 early-phase clinical trial centers (CLIP2) certified by the French National Cancer Institute. Sociodemographic, socioeconomic and medical data were collected. Univariate logistic regression models were carried out to estimate odds ratios and 90% confidence intervals associated with the effect of each study variable. A multivariate logistic regression model was built to explore the independent factors associated with the administration of the experimental treatment (C1D1). A post hoc analysis was carried out excluding female cancer patients. RESULTS: Between 2015 and 2016, 1355 patients referred from 11 CLIP2 centers in France were included in the study. Eight hundred and forty-eight patients received C1D1 (73%) and 320 patients (27%) were screening failure. Median age was 58 years (range 17-97 years) and 667 patients (54%) were female. Most patients had a metastatic disease (n = 751, 87%). In the multivariate logistic regression analysis, the significant independent factors associated with C1D1 were male sex, initial care received in a hospital with an early-phase unit and living in wealthy metropolitan areas (P values <0.05). In the post hoc analysis, the sex factor was no longer significant [odds ratio = 1.21 (95% confidence interval 0.86-1.70), P value = 0.271]. CONCLUSIONS: This study investigated the factors producing social inequalities in the context of early-phase clinical trials in oncology. Our research highlights factors of sex, care pathway and geographic location. Gynecological cancer was found to impact C1D1 significantly, unlike breast cancer. The results of this study should contribute to improve patient access to early-phase clinical trials.

A phase 1b study of crenigacestat (LY3039478) in combination with gemcitabine and cisplatin or gemcitabine and carboplatin in patients with advanced or metastatic solid tumors.

BACKGROUND: Notch signaling plays an integral role in development and tissue homeostasis. Inhibition of Notch signaling has been identified as a reasonable target for oncotherapy. Crenigacestat (LY3039478) is a potent Notch inhibitor that decreases Notch signaling and its downstream biologic effects. METHODS: I6F-MC-JJCD was a multicenter, nonrandomized, open-label, phase 1b study with 5 separate, parallel dose escalations in patients with advanced or metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in pre-specified tumor types. This manuscript reports on 2 of 5 groups. The primary objective was to determine the recommended phase 2 dose of crenigacestat combined with other anticancer agents (gemcitabine/cisplatin or gemcitabine/carboplatin). Secondary objectives included evaluation of safety, tolerability, preliminary efficacy, and pharmacokinetics. RESULTS: Patients (N = 31) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 6 patients. The recommended phase 2 dose for crenigacestat was 50 mg TIW in Part 1 (combined with gemcitabine/cisplatin) and not established in Part 2 (combined with gemcitabine/carboplatin) due to poor tolerability. Patients had at least one treatment-emergent adverse event (TEAE), and most had Grade ≥ 3 TEAEs. Over 50% of the patients experienced gastrointestinal disorders (Grade ≥ 3). No patient had complete response; 5 patients had a partial response. Disease control rates were 62.5% (Part 1) and 60.0% (Part 2). CONCLUSION: This study demonstrated that the Notch inhibitor, crenigacestat, combined with different anticancer agents (gemcitabine, cisplatin, and carboplatin) was poorly tolerated and resulted in disappointing clinical activity in patients with advanced or metastatic solid tumors. CLINICALTRIALS: gov Identification Number: NCT02784795.

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Access to early-phase clinical trials in older patients with cancer in France: the EGALICAN-2 study.

BACKGROUND: Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients. PATIENTS AND METHODS: During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute. RESULTS: A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were <70 years and 233 patients (17.7%) were >70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045). CONCLUSIONS: Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent.

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials.

BACKGROUND: The prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS). PATIENTS AND METHODS: This retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020. RESULTS: Overall, 199 patients accounted for 214 inclusions in advanced STS. The most frequent histotypes were well-differentiated/dedifferentiated liposarcomas (n = 55), leiomyosarcomas (n = 53), synovial sarcomas (n = 22), undifferentiated pleomorphic sarcomas (n = 15), angiosarcomas (n = 12), and myxoid liposarcomas (n = 10). The median PFS was 2.8 months (95% confidence interval 2.7-4.1 months). The median PFS in the first, second, and later lines was 8.3, 5.4, and 2.6 months, respectively (P = 0.00015). The median PFS was 2.8 months in case of molecular screening, 4.1 months in case of histology-driven screening, and 1.6 months (P = 0.00014) in the absence of either screening modalities. In univariate analysis, histotype (P = 0.026), complex genomics (P = 0.008), number of prior lines (P < 0.001), prior anthracyclines (P < 0.001), number of metastatic sites (P = 0.003), liver metastasis (P < 0.001), lung metastasis (P < 0.001), absence of molecular or histology-driven screening (P < 0.001), first-in-human trials (P < 0.001), dose-escalation cohorts (P = 0.011), and Royal Marsden Hospital (RMH) score >1 (P < 0.001) were significantly associated with shorter PFS. In multivariate analysis, independent prognostic factors for shorter PFS were myxoid liposarcoma (P = 0.031), ≥2 prior lines of treatment (P = 0.033), liver metastasis (P = 0.007), and RMH score >2 (P = 0.006). Factors associated with improved PFS were leiomyosarcomas (P = 0.010), molecular screening (P = 0.025), and histology-driven screening (P = 0.010). The median overall survival rates were 36.3, 12.6, and 9.2 months in the first, second, and later lines, respectively (P = 0.0067). The grade 3-4 toxicity rate was 36%. CONCLUSIONS: Early phase trials provide an active therapeutic option for STS, even in first-line settings. Molecular screening and histology-driven trials further improve the clinical benefit.

Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance.

BACKGROUND: Immune checkpoint blockers (ICBs) are now widely used in oncology. Most patients, however, do not derive benefit from these agents. Therefore, there is a crucial need to identify novel and reliable biomarkers of resistance to such treatments in order to prescribe potentially toxic and costly treatments only to patients with expected therapeutic benefits. In the wake of genomics, the study of proteins is now emerging as the new frontier for understanding real-time human biology. PATIENTS AND METHODS: We analyzed the proteome of plasma samples, collected before treatment onset, from two independent prospective cohorts of cancer patients treated with ICB (discovery cohort n = 95, validation cohort n = 292). We then investigated the correlation between protein plasma levels, clinical benefit rate, progression-free survival and overall survival by Cox proportional hazards models. RESULTS: By using an unbiased proteomics approach, we show that, in both discovery and validation cohorts, elevated baseline serum level of leukemia inhibitory factor (LIF) is associated with a poor clinical outcome in cancer patients treated with ICB, independently of other prognostic factors. We also demonstrated that the circulating level of LIF is inversely correlated with the presence of tertiary lymphoid structures in the tumor microenvironment. CONCLUSION: This novel clinical dataset brings strong evidence for the role of LIF as a potential suppressor of antitumor immunity and suggests that targeting LIF or its pathway may represent a promising approach to improve efficacy of cancer immunotherapy in combination with ICB.

First record of Bulimulus tenuissimus (Mollusca) as potential experimental intermediate host of Angiostrongylus cantonensis (Nematoda) / Primeiro registro de Bulimulus tenuissimus (Mollusca) como hospedeiro intermediário de Angiostrongylus cantonensis (Nematoda)

Abstract Snails are essential to complete the life cycle of the metastrongylid nematode Angiostrongylus cantonensis, the causative agent of infections in domestic and wild animals, mainly rodents, and also of neural angiostrongyliasis or eosinophilic meningitis in humans. There are many reports of mollusks that can act as intermediate hosts of this parasite, especially freshwater snails and the African giant Achatina fulica. The terrestrial gastropod Bulimulus tenuissimus is widely distributed in Brazil and other species of the same genus occur in Brazil and other countries, overlapping regions in which there are reports of the occurrence of A. cantonensis and angiostrongyliasis. In spite of this, there are no records in the literature of this species performing the role of intermediate host to A. cantonensis. The present study analyzed the experimental infection with first-stage larvae of A. cantonensis, under laboratory conditions, of B. tenuissimus, by using histology and electron microscopy techniques. Three weeks after exposure to L1 larvae, it was possible to recover L3 larvae in small numbers from the infected snails. Developing larvae were observed in the cephalopedal mass (foot), ovotestis, and mantle tissues, being located inside a granulomatous structure composed of hemocyte infiltration, but there was no calcium or collagen deposition in these structures in significant amounts. In the third week post exposure, it was possible observe a sheath around the developing larvae. The infected snails presented reduction in the fibrous muscular tissue in the foot region, loss of the acinar organization in the digestive gland, with increase of amorphous material inside the acini and loss of epithelial pattern of nuclear organization in the acinar cells. However, the ovotestis seemed unaffected by the infection, since there was a large number of developing oocytes and spermatozoa in different stages of formation. The digestion of infected snails allows us the third-stage recovery rate of 17.25%, at 14 days post exposure to the L1. These L3 recovered from B. tenuissimus were used to infect rats experimentally, and 43 days post infection first-stage (L1) larvae of A. cantonensis were recovered from fresh feces. The results presented constituted the first report of the role of B. tenuissimus as an experimental intermediate host to A. cantonensis and shed some light on a possible problem, since the overlapping distribution of B. tenuissimus and A. cantonensis in Brazil and other countries where different species of Bulimulus occur enables the establishment and maintenance of the life cycle of this parasite in nature, with wild rodents as reservoirs, acting as a source of infection to humans, causing neural angiostrongyliasis.

Resumo Os moluscos são um requisito essencial para a conclusão do ciclo de vida pelo nematoide metastrogilídeo Angiostrongylus cantonensis, o agente causador de infecções em animais domésticos e selvagens, principalmente roedores, e também de angiostrongilíase neural ou meningite eosinofílica em humanos. Há muitos relatos de moluscos que podem atuar como hospedeiro para este parasito, sendo o foco dado aos moluscos de água doce e no gigante africano Achatina fulica. O gastrópode terrestre Bulimulus tenuissimus é amplamente distribuído no território brasileiro e há outras espécies do mesmo gênero que ocorrem no Brasil e outros países, sobrepondo-se às regiões em que há relatos à ocorrência de A. cantonensis e angiostornigilíase. Apesar disso, não há registro na literatura, acerca desta espécie como hospedeiro intermediário para A. cantonensis. O presente estudo teve como objetivo verificar a possibilidade de infectar experimentalmente, utilizando larvas L1 de A. cantonensis, em condições laboratoriais, o molusco B. tenuissimus, utilizando técnicas de histologia e microscopia eletrônica. Três semanas após a exposição às larvas L1, foi possível recuperar larvas L3 dos moluscos infectados, em pequena quantidade. As larvas em desenvolvimento foram observadas na massa cefalopediosa (pé), ovotestis e nos tecidos do manto, sendo localizadas dentro de uma estrutura granulomatosa constituída por infiltração hemocitária, mas não houve deposição de cálcio ou colágeno nessas estruturas em quantidade significativa. Na terceira semana pós exposição, foi possível observar uma bainha ao redor das larvas em desenvolvimento. Os caracóis infectados apresentaram redução no tecido muscular fibroso na região do pé, perda da organização acinar na glândula digestiva, com aumento de material amorfo dentro dos ácinos e perda do padrão epitelial da organização nuclear nas células acinares. No entanto, o ovotestis, pareceu não ser afetado pela infecção, uma vez que houve um grande número de oócitos em desenvolvimento e espermatozóides em diferentes estágios de formação. A digestão dos moluscos infectados nos permitiu a recuperação de larvas de terceiro estágio (17,25%), aos 14 dias após a exposição à L1 de A. cantonensis . Estas L3 recuperadas de B. tenuissimus foram utilizados para infectar ratos experimentalmente, e 43 dias após a infecção, as larvas do primeiro estágio (L1) foram recuperadas de fezes frescas. Os resultados apresentados representam o primeiro registro do papel de B. tenuissimus como hospedeiro intermediário experimental de A. cantonensis e trazem alguma luz a um problema, até então silencioso, uma vez que a sobreposição da distribuição de B. tenuissimus e A. cantonensis no Brasil, e outros países, onde as diferentes espécies de Bulimulus ocorrem, torna possível o estabelecimento e manutenção do ciclo de vida deste parasito na natureza, com roedores selvagens como reservatório, agindo como fonte de infecção para humanos e causando a angiostrongilíase neural.

First record of Bulimulus tenuissimus (Mollusca) as potential experimental intermediate host of Angiostrongylus cantonensis (Nematoda).

Snails are essential to complete the life cycle of the metastrongylid nematode Angiostrongylus cantonensis, the causative agent of infections in domestic and wild animals, mainly rodents, and also of neural angiostrongyliasis or eosinophilic meningitis in humans. There are many reports of mollusks that can act as intermediate hosts of this parasite, especially freshwater snails and the African giant Achatina fulica. The terrestrial gastropod Bulimulus tenuissimus is widely distributed in Brazil and other species of the same genus occur in Brazil and other countries, overlapping regions in which there are reports of the occurrence of A. cantonensis and angiostrongyliasis. In spite of this, there are no records in the literature of this species performing the role of intermediate host to A. cantonensis. The present study analyzed the experimental infection with first-stage larvae of A. cantonensis, under laboratory conditions, of B. tenuissimus, by using histology and electron microscopy techniques. Three weeks after exposure to L1 larvae, it was possible to recover L3 larvae in small numbers from the infected snails. Developing larvae were observed in the cephalopedal mass (foot), ovotestis, and mantle tissues, being located inside a granulomatous structure composed of hemocyte infiltration, but there was no calcium or collagen deposition in these structures in significant amounts. In the third week post exposure, it was possible observe a sheath around the developing larvae. The infected snails presented reduction in the fibrous muscular tissue in the foot region, loss of the acinar organization in the digestive gland, with increase of amorphous material inside the acini and loss of epithelial pattern of nuclear organization in the acinar cells. However, the ovotestis seemed unaffected by the infection, since there was a large number of developing oocytes and spermatozoa in different stages of formation. The digestion of infected snails allows us the third-stage recovery rate of 17.25%, at 14 days post exposure to the L1. These L3 recovered from B. tenuissimus were used to infect rats experimentally, and 43 days post infection first-stage (L1) larvae of A. cantonensis were recovered from fresh feces. The results presented constituted the first report of the role of B. tenuissimus as an experimental intermediate host to A. cantonensis and shed some light on a possible problem, since the overlapping distribution of B. tenuissimus and A. cantonensis in Brazil and other countries where different species of Bulimulus occur enables the establishment and maintenance of the life cycle of this parasite in nature, with wild rodents as reservoirs, acting as a source of infection to humans, causing neural angiostrongyliasis.

Outcomes of long-term responders to anti-programmed death 1 and anti-programmed death ligand 1 when being rechallenged with the same anti-programmed death 1 and anti-programmed death ligand 1 at progression.

BACKGROUND: Long-term responders have been observed with anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD(L)1). Optimal duration of therapy in responding and stable disease (SD) patients is unclear with various attitudes encompassing treatment until progression disease, stopping therapy after a defined timeframe. PATIENTS AND METHODS: We report the experience of 13 patients who discontinued immune checkpoint inhibitor in phase I trials as per protocol while experiencing a tumour-controlled disease. According to protocols, patients could restart the same immunotherapy if radiological or clinical progression occurred. RESULTS: Patients were treated for colorectal microsatellite instability-high genotype (n = 5), urothelial carcinoma (n = 3), melanoma (n = 2), non-small-cell lung cancer (n = 2) and triple-negative breast cancer (n = 1) for a median time of 12 months (range 10.6-12). Patients achieved 1 (8%) complete response, 10 (77%) partial response (PR) and 2 (15%) SD. The median progression-free survival 1 (PFS1) defined as the time from the first infusion until progression was 24.4 months (range 15.8-49). The median time free-treatment after discontinuation was 12.6 months (range 4-39.7). Eight patients experienced disease progression and were retreated. Best responses observed after rechallenging were 2 PR (25%) and 6 SD (75%). Median PFS2 defined from the first day of retreatment until disease progression or the last news was 12.9 months (range 5-35.4). No grade 3/4 events occurred during the study period. CONCLUSION: Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results.

First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer.

Background: Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods: This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results: A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aß, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion: Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID: NCT01695005.

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806.

Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours.

BACKGROUND: The development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance. METHODS: All cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Case-control analysis was performed in OPs (patients ≥ 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes. RESULTS: Among the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade III-IV IrAEs. Cumulative incidence of grade I-II IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade III-IV IrAEs (p = 0.50). Older age was not associated with lower dose intensity of treatment (p = 0.14). No significant difference was observed between OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94-2.11] p = 0.09) or median overall survival (HR 0.92, 95% CI [0.61-1.39] p = 0.77). CONCLUSION: Immune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials.

Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours.

BACKGROUND: Preclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab. METHODS: Temsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150-250 mg/m2, until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation. RESULTS: Among 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m2 and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration. CONCLUSIONS: Combination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development.

[Management of a progressing prostate cancer: results of a national study]. / Surveillance et adaptation de la stratégie thérapeutique en cas de progression de la maladie dans le cancer de la prostate avancé : résultats d'une enquête nationale.

INTRODUCTION: The introduction of new treatments in metastatic castration resistant prostate cancer (mCRPC) requires a close follow-up to detect a progression and then to adapt the treatment. In that context, a national survey was proposed to a group of experts and the aim was to identify the modalities of surveillance in different clinical situations. METHODS: A questionnaire was sent to 1464 urologists, medical oncologists and radiotherapists, about a clinical case; it was about a patient presenting a prostate cancer, evolving from a biologic progression after radical prostatectomy to a situation of metastasis resistant to the castration. The questionnaire contained ten questions about reasons of changing treatment because of progression, and about modalities of the follow-up. RESULTS: A total of 318 questionnaires were analyzed (response rate of 22%). The results showed comparable practices between the different types of specialists, even if a more frequent rhythm of surveillance was reported by medical oncologists and radiotherapists. At progression after radical prostatectomy, a clinical and biological surveillance was generally realized every 3 or 6 months, and imaging exams were done on demand. Then, as the cancer progresses, the surveillance became systematic and more and more close, with imaging done every 3 months or on demand. While the definition of progression was essentially based on PSA testing at the beginning of the castration resistance, it then combines different clinical, biological and radiological criteria. CONCLUSIONS: There are few recommendations available about follow-up of patients with a mCRPC. In that survey, the oncologists and urologists reported a more intensive rhythm of surveillance as the prostate cancer progresses. LEVEL OF EVIDENCE: 4.

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II). Results: Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions: The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.