Oncology Daily Report: 01/09/2024
Carcinomas: Breast Cancer
The first study was a phase 2, randomized, multicenter, open-label trial(1). Its main purpose was to evaluate the safety and efficacy of efbemalenograstim alfa, a drug intended for neutrophil support in women with breast cancer undergoing myelosuppressive chemotherapy. The study's ClinicalTrials.gov identifier is NCT01648322, and it commenced on July 19, 2012.
The population under investigation comprised 232 patients who were undergoing up to four cycles of chemotherapy. These patients were divided based on their chemotherapy regimen: 141 patients received docetaxel and cyclophosphamide (TC), while 91 patients were administered docetaxel, doxorubicin, and cyclophosphamide (TAC). The intervention under investigation involved the administration of efbemalenograstim alfa at varying dosages: 80, 240, or 320 µg/kg for patients on the TC regimen and 240 or 320 µg/kg for those on the TAC regimen. Efbemalenograstim alfa was administered on Day 2 of each chemotherapy cycle. The control group in this study received pegfilgrastim at a dose of 6 mg, also on Day 2 of each cycle.
The results of the study indicated that efbemalenograstim alfa was non-inferior to pegfilgrastim in terms of the duration of moderate and severe neutropenia (absolute neutrophil count [ANC] < 1.0 × 10(9)/L) in the first cycle of TAC chemotherapy. The mean duration of neutropenia for patients treated with 240 µg/kg and 320 µg/kg efbemalenograstim alfa was 2.1 days (with a standard deviation [SD] of 1.58) and 2.1 days (SD of 1.46) respectively, compared to 1.8 days (SD of 1.28) for those receiving pegfilgrastim. The difference in duration between efbemalenograstim alfa and pegfilgrastim was reported as 0.3 days, with a 95% confidence interval (CI) of -0.4 to 1.1 days.
Additionally, the ANC nadir (the lowest point) occurred between Days 7-8 of the first TAC cycle. The mean ANC nadir values were 0.68 × 10(9)/L (SD of 1.064), 0.86 × 10(9)/L (SD of 1.407), and 0.78 × 10(9)/L (SD of 1.283) for the 240 µg/kg, 320 µg/kg efbemalenograstim alfa, and pegfilgrastim groups, respectively. The time to ANC recovery post-nadir was 2.0-2.4 days for TAC patients treated with efbemalenograstim alfa and 1.9 days for those treated with pegfilgrastim. The incidence of moderate to severe neutropenia was similar across all treatment groups (76%-77% of patients), as was the incidence of severe neutropenia (ANC < 0.5 × 10(9)/L; 63%-72%).
The safety profile of efbemalenograstim alfa was found to be similar to that of pegfilgrastim. Notably, febrile neutropenia occurred in 4 patients (1.8% of the study population), with 2 cases each in the 320 µg/kg efbemalenograstim alfa group and the pegfilgrastim group. None of these events were considered related to the study drug.
In conclusion, efbemalenograstim alfa demonstrated comparable efficacy and safety to pegfilgrastim, suggesting it as a viable alternative for neutrophil support in this patient population.
Reference
Glaspy J, Bondarenko I, Krasnozhon D, Rutty D, Chen J, Fu Y, Wang S, Hou Q, Li S. Efbemalenograstim alfa not inferior to pegfilgrastim in providing neutrophil support in women with breast cancer undergoing myelotoxic chemotherapy: results of a phase 2 randomized, multicenter, open-label trial. Support Care Cancer. 2024 Jan 9;32(2):91. doi: 10.1007/s00520-023-08260-x. PMID: 38194162; PMCID: PMC10776461.
Carcinomas: Breast Cancer
The second study focused on the anti-proliferative effects of Boswellia serrata, a frankincense extract, in patients with breast cancer (1). This was a Phase Ia clinical trial, characterized as a "window of opportunity" study, primarily designed to evaluate the biologic activity and safety of the intervention. The study's design involved treating patients with invasive breast cancer pre-operatively using Boswellia serrata, administered orally at a dosage of 2400 mg/day until the night before surgery. The duration of treatment varied among patients, with a median of 11 days (standard deviation of 6 days; range: 5-23 days).
The population under investigation comprised patients with invasive breast cancer. In this study, 22 patients were enrolled, 20 of whom received the treatment. For the purpose of analysis, 18 patients had sufficient tissue for immunohistochemistry (IHC) assessment. The intervention's effects were evaluated by comparing changes in tumor proliferation and apoptosis in tissue samples taken before and after the treatment. The assessment involved using a tunnel assay and immunohistochemistry staining with Ki-67 antibodies.
A key aspect of the study's methodology was the inclusion of a control group for comparative analysis. This control group was a non-intervention retrospective arm consisting of tissue specimens from untreated breast cancer patients. The study compared the change in proliferation and apoptosis between diagnostic core specimens and surgical specimens in both the control and treatment groups. The statistical analysis was conducted using a two-tailed paired t-test.
The results of the study were notable. In the control group (n = 18), there was an observed increase in the percent change in proliferation from core biopsy to surgical excision, quantified at 54.6 ± 21.4%. Conversely, in the Boswellia serrata-treated group (also n = 18), there was a reduction in proliferation between core biopsy and excision, measured at 13.8 ± 11.7%. This difference in proliferation changes between the control and treated groups was statistically significant, with a p-value of 0.008. However, there was no observed difference in the change in apoptosis between the two groups. Additionally, the study reported no serious adverse events related to the drug, suggesting a favorable safety profile.
In conclusion, the study demonstrated that Boswellia serrata could inhibit breast cancer proliferation effectively and was well-tolerated in patients, as evidenced in this Phase Ia window of opportunity trial.
Reference
Valente IVB, Garcia D, Abbott A, Spruill L, Siegel J, Forcucci J, Hanna G, Mukherjee R, Hamann M, Hilliard E, Lockett M, Cole DJ, Klauber-DeMore N. The anti-proliferative effects of a frankincense extract in a window of opportunity phase ia clinical trial for patients with breast cancer. Breast Cancer Res Treat. 2024 Jan 9. doi: 10.1007/s10549-023-07215-4. Epub ahead of print. PMID: 38194131.
CNS Cancers: Glioblastoma
The PARADIGM trial, a phase I dose escalation study, investigated the combination of olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma (1). This study specifically targeted a population of patients who were either aged 70 or over with a World Health Organization Performance Status (WHO PS) of 0-1, or aged 18-69 with a PS of 2, and were unsuitable for radical treatment. The intervention under investigation was olaparib, an oral inhibitor of the poly(ADP-ribose) polymerase (PARP) enzyme, administered alongside short-course radiotherapy (40 Gy in 15 fractions).
The primary outcome of the study was to establish the recommended phase 2 dose (RP2D) of olaparib. Secondary endpoints included evaluating the safety and tolerability of the treatment, as well as assessing its impact on overall survival (OS), progression-free survival (PFS), and cognitive function, the latter measured by the mini-mental state examination (MMSE).
A total of 16 patients were enrolled in the study, of which 56.25% were male, with a median age of 71.5 years (ranging from 44 to 78 years), and 75% had a PS of 0-1. The study reported one case of dose-limiting toxicity (grade 3 agitation), but the maximum tolerated dose was not reached. Consequently, the RP2D of olaparib was determined to be 200 mg taken twice daily.
In terms of outcomes, the median overall survival was 10.8 months (with an 80% confidence interval [CI] of 7.3-11.4 months), and the median progression-free survival was 5.5 months (80% CI: 3.9-5.9 months). The results also indicated that the combination of olaparib and radiotherapy did not adversely affect cognitive function, as demonstrated by the MMSE plots.
The study concluded that olaparib could be safely combined with hypofractionated brain radiotherapy and was well tolerated in the patient population under study. These findings led to the initiation of a randomized phase II study and support the potential for future trials involving PARP inhibitors in combination with radiotherapy for patients with brain tumors.
Reference
Derby S, Jackson MR, Williams K, Stobo J, Kelly C, Sweeting L, Shad S, Herbert C, Short SC, Williamson A, James A, Nowicki S, Bulbeck H, Chalmers AJ. Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. Int J Radiat Oncol Biol Phys. 2024 Jan 9:S0360-3016(24)00015-4. doi: 10.1016/j.ijrobp.2024.01.011. Epub ahead of print. PMID: 38211641.
Gastrointestinal Cancers: Pancreatic and Colorectal Cancers
The study titled "Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial" focused on investigating the efficacy and safety of a cancer vaccine, ELI-002 2P, in the treatment of pancreatic and colorectal cancers (1). These cancers are often characterized by KRAS mutations and are challenging to cure when tumor DNA or protein persists or recurs after initial therapy. The study was designed as a phase 1 clinical trial.
The population under investigation comprised 25 patients, with 20 having pancreatic cancer and five having colorectal cancer. All these patients were positive for minimal residual mutant KRAS (mKRAS) disease, as evidenced by circulating tumor DNA (ctDNA) and/or serum tumor antigen levels, following their locoregional treatment.
The intervention under investigation was the fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909. ELI-002 2P, the cancer vaccine being tested, aims to enhance lymph node delivery and immune response. It does this by using an amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with a CpG oligonucleotide adjuvant (Amph-CpG-7909).
The primary endpoints of the study were safety and determining the recommended phase 2 dose (RP2D). Secondary endpoints included tumor biomarker response, measured through longitudinal ctDNA or tumor antigen levels. The exploratory endpoints included immunogenicity and relapse-free survival (RFS).
In terms of results, no dose-limiting toxicities were observed, and the RP2D was established at 10.0 mg of Amph-CpG-7909. Notably, direct ex vivo mKRAS-specific T cell responses were observed in 21 of the 25 patients (84%), with 59% showing responses in both CD4(+) and CD8(+) T cells. Tumor biomarker responses were also observed in 84% of the patients, and biomarker clearance was noted in 24% (six patients, split equally between pancreatic and colorectal cancer patients). The median RFS was reported as 16.33 months. Efficacy correlated significantly with T cell responses: patients with T cell responses above the median fold increase over baseline showed a median tumor biomarker reduction of -76.0% versus -10.2% and a median RFS not reached versus 4.01 months.
The study concluded that ELI-002 2P was safe and induced significant T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors.
Reference
Pant S, Wainberg ZA, Weekes CD, Furqan M, Kasi PM, Devoe CE, Leal AD, Chung V, Basturk O, VanWyk H, Tavares AM, Seenappa LM, Perry JR, Kheoh T, McNeil LK, Welkowsky E, DeMuth PC, Haqq CM, O'Reilly EM. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat Med. 2024 Jan 9. doi: 10.1038/s41591-023-02760-3. Epub ahead of print. PMID: 38195752.
Gynecological Cancers: Ovarian Cancer
This study, titled "Peritonectomy and resection of mesentery during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer: A phase I-II trial," focused on evaluating the surgical technique, feasibility, efficacy, and safety of peritonectomy and/or resection of mesentery (P-Rme) during Visceral-Peritoneal Debulking (VPD) in patients diagnosed with stage IIIC-IV ovarian cancer (1). The study was designed as a phase I-II trial.
The population under investigation comprised patients with FIGO stage IIIC-IV ovarian cancer. From April 2009 to December 2022, a total of 687 patients with this condition underwent VPD. Of these, 129 patients, accounting for 18.7% of the total, had extensive disease on the mesentery and subsequently underwent the P-Rme procedure.
The intervention under investigation in this study was the P-Rme procedure performed during VPD. This intervention was assessed based on the feasibility, which was determined by the number of procedures successfully completed, efficacy, measured as the rate of Complete Resection (CR), and safety, defined by the intra- and post-operative morbidity rate specifically associated with these procedures.
Out of the 129 patients who underwent P-Rme, 82 underwent peritonectomy (P-me), 47 underwent resection of mesentery (R-me), and 23 underwent both procedures. The study reported a 100% success rate in achieving Complete Resection in all 129 patients. The intra-operative morbidity was reported at 3.8%, with 5 out of 129 patients experiencing small bowel loop surgical devascularization, requiring additional surgery.
Regarding follow-up, the median duration was 64 months. During this period, survival outcomes for patients who underwent the P-Rme procedure were found to be similar to those in the control group.
In conclusion, the study found that nearly 20% of patients undergoing VPD required P-Rme to achieve a Complete Resection. The procedure was deemed safe and effective, with a high rate of CR and no specific post-operative complications, although 3.8% of patients required unplanned additional surgery related to the procedure.
Reference
Tozzi R, Noventa M, Spagnol G, De Tommasi O, Coldebella D, Tamagnini M, Bigardi S, Saccardi C, Marchetti M. Peritonectomy and resection of mesentery during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer: A phase I-II trial. Eur J Surg Oncol. 2024 Jan 9;50(2):107957. doi: 10.1016/j.ejso.2024.107957. Epub ahead of print. PMID: 38219700.
Lymphomas: Follicular Lymphoma
This was a report of the long-term follow-up of the RESORT study (E4402), which was a randomized phase III clinical trial initiated in 2003 by the Eastern Cooperative Oncology Group (1). The study's primary aim was to compare two different rituximab dosing strategies for patients with previously untreated low-tumor burden follicular lymphoma.
In terms of study design, the trial was randomized and focused on two distinct rituximab dosing strategies. The population under investigation comprised patients with low-tumor burden follicular lymphoma who had not received prior treatment. A total of 299 rituximab-responsive patients participated in the study. These patients were randomly assigned to one of two groups: a retreatment rituximab (RR) strategy or a maintenance rituximab (MR) strategy. Each dosing strategy was continued until treatment failure.
The primary endpoint of the study was time to treatment failure (TTF). In the original report, no significant difference was observed in TTF between the two dosing strategies. However, the long-term follow-up report, as presented in the provided text, focuses on secondary endpoints, including time to first cytotoxic therapy, duration of response, and overall survival (OS).
The results of the study, after a follow-up duration of 7 years, indicated that 83% of patients in the MR group had not required first chemotherapy, compared to 63% in the RR group. This result was statistically significant, with a hazard ratio of 2.37 (95% CI, 1.5 to 3.76). Additionally, 71% of patients in the MR group remained in their first remission after 7 years, compared to 37% in the RR group. Despite these significant differences in the time to first chemotherapy and duration of the first remission, there was no difference in overall survival at 10 years between the two groups (83% for MR vs 84% for RR).
In conclusion, the long-term data from the RESORT study confirmed that prolonged maintenance rituximab does not confer an overall survival advantage in patients with low-tumor burden follicular lymphoma. The study provided valuable insights into the effectiveness of different rituximab dosing strategies in this patient population.
Reference
Kahl BS, Jegede OA, Peterson C, Swinnen LJ, Habermann TM, Schuster SJ, Weiss M, Fishkin PA, Fenske TS, Williams ME. Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol. 2024 Jan 9:JCO2301912. doi: 10.1200/JCO.23.01912. Epub ahead of print. PMID: 38194625.
Lymphomas: Follicular Lymphoma
The study titled "Durable Response After Tisagenlecleucel in Adults With Relapsed/Refractory Follicular Lymphoma: ELARA Trial Update" focused on the efficacy and safety of tisagenlecleucel in treating adults with relapsed/refractory follicular lymphoma (FL) (1). This investigation was structured as a Phase II trial, identified as the ELARA trial with the ClinicalTrials.gov identifier NCT03568461.
The population targeted in this study consisted of 97 patients diagnosed with relapsed/refractory FL, specifically grades 1-3A. These individuals were chosen based on their history of having undergone at least two lines of therapy or having relapsed following an autologous stem cell transplant. The intervention under examination was the infusion of tisagenlecleucel, administered at a dose range of 0.6 to 6×10^8 CAR+ viable T cells. Notably, the study allowed for bridging chemotherapy, which is a significant detail in understanding the treatment regimen.
The study reported various significant results. The median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached after a median follow-up of 29 months. However, estimated 24-month PFS, DOR, and OS rates were 57.4% (95% CI, 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. The complete response rate was 68.1% (95% CI, 57.7-77.3), and the overall response rate was 86.2% (95% CI, 77.5-92.4). Importantly, no new safety signals or treatment-related deaths were reported, indicating a favorable safety profile.
Additionally, the study conducted exploratory biomarker analyses. It found that low levels of tumor-infiltrating LAG3+CD3+ exhausted T-cells and higher baseline levels of naïve CD8+ T-cells were associated with improved outcomes. This highlights a potential link between specific immune cell profiles and the efficacy of tisagenlecleucel.
In conclusion, tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in patients with relapsed/refractory FL during the extended follow-up period of 29 months in the ELARA trial. This trial adds to the growing body of evidence supporting the use of tisagenlecleucel in this challenging patient population.
Reference
Dreyling M, Fowler NH, Dickinson M, Martínez-López J, Kolstad A, Butler J, Ghosh M, Popplewell L, Chavez JC, Bachy E, Kato K, Harigae H, Kersten MJ, Andreadis CB, Riedell PA, Ho PJ, Perez-Simon JA, Chen AI, Nastoupil LJ, von Tresckow B, Ferreri AJ, Teshima T, Patten PE, McGuirk JP, Petzer AL, Offner F, Viardot A, Zinzani PL, Malladi R, Paule I, Zia A, Awasthi R, Han X, Germano D, O'Donovan DS, Ramos RJ, Maier HJ, Masood A, Thieblemont C, Schuster SJ. Durable Response After Tisagenlecleucel in Adults With Relapsed/Refractory Follicular Lymphoma: ELARA Trial Update. Blood. 2024 Jan 9:blood.2023021567. doi: 10.1182/blood.2023021567. Epub ahead of print. PMID: 38194692.
Lymphomas: Post in-situ Vaccination
This study was a clinical trial designed to evaluate the efficacy and biological mechanisms of in situ vaccination (ISV) in patients with low-grade lymphoma (1). This phase 1/2 trial combined an intratumoral toll-like receptor 9 (TLR9) agonist with local low-dose radiation and ibrutinib, an inhibitor of B- and T-cell kinases. The focus was on patients with low-grade lymphoma, a type of cancer that affects the lymphatic system.
The intervention under investigation involved the administration of an intratumoral TLR9 agonist along with local low-dose radiation and ibrutinib. This combination was chosen to stimulate an immune response against tumor-associated antigens at one tumor site, with the intention of initiating a systemic response to combat the disease throughout the body.
The overall response rate to the treatment was 50%, including one complete response. Additionally, all patients experienced tumor reduction at distant sites, indicating a systemic effect of the treatment.
The results of the study highlighted several important findings. Adverse events were predominantly low grade, suggesting a favorable safety profile for the treatment. The single-cell analyses of serial fine needle aspirates from injected and uninjected tumors provided insights into the mechanisms of response. Key findings included lower CD47 and higher major histocompatibility complex class II expression on tumor cells, enhanced effector function of T-cells and natural killer cells, and reduced immune suppression from transforming growth factor β and inhibitory T regulatory 1 cells. Notably, while changes at the local injected site were more pronounced, alterations at distant uninjected sites were more frequently associated with clinical responses. Functional immune response assays and tracking of T-cell receptor sequences demonstrated treatment-induced tumor-specific T-cell responses, indicating that induction of immune effectors and reversal of negative regulators were both important for clinically meaningful tumor responses.
Overall, the study provided valuable insights into the potential of ISV as a therapeutic approach in low-grade lymphoma, showing promising response rates and systemic effects, with a focus on detailed immunological analysis to understand the underlying mechanisms of response.
Reference
Shree T, Haebe S, Czerwinski DK, Eckhert E, Day G, Sathe A, Grimes S, Frank MJ, Maeda LS, Alizadeh AA, Advani R, Hoppe RT, Long SR, Martin B, Ozawa MG, Khodadoust MS, Ji HP, Levy R. A clinical trial of therapeutic vaccination in lymphoma with serial tumor sampling and single-cell analysis. Blood Adv. 2024 Jan 9;8(1):130-142. doi: 10.1182/bloodadvances.2023011589. PMID: 37939259; PMCID: PMC10787245.
Lymphomas: Large B-cell Lymphoma
This study focused on the clinical safety and efficacy of a specific chimeric antigen receptor (CAR) T cell therapy, named 7×19 CAR-T cells, for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) (1). This therapy involves CD19-specific CAR-T cells that are capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement.
The study was designed as a phase 1 and expansion phase trial. It aimed to assess the safety and feasibility of the 7×19 CAR-T cell therapy in patients diagnosed with R/R LBCL. The study's primary population under investigation were patients who had relapsed or refractory large B-cell lymphoma.
In terms of intervention, patients received the 7×19 CAR-T cell therapy, with dosages ranging from 0.5×10(6) to 4.0×10(6) cells per kilogram of body weight.
A total of 39 patients with R/R LBCL participated in the study. During the dose-escalation phase, no dose-limiting toxicities were observed. The safety profile was further highlighted by the occurrence of Grade 3 cytokine release syndrome in 5 patients (12.8%) and Grade 3 or higher neurotoxicity in 4 patients (10.3%).
Regarding the study's results, the overall response rate at 3 months post-single infusion was 79.5%, with a complete remission rate of 56.4% and a partial response rate of 23.1%. The median progression-free survival was documented at 13 months. The median overall survival had not been reached at the time of the report, with an estimated 2-year survival rate of 53.8% (95% confidence interval, 40.3% to 72.0%).
The study reported a median follow-up duration of 32 months. The long-term follow-up data from this multicenter clinical study suggested that the 7×19 CAR-T cells can induce durable responses in patients with R/R LBCL, showing a median overall survival of greater than 2 years, and they have a manageable safety profile.
Reference
Lei W, Zhao A, Liu H, Yang C, Wei C, Guo S, Chen Z, Guo Q, Li L, Zhao M, Wu G, Ouyang G, Liu M, Zhang J, Gao J, Qian W. Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma. Cell Discov. 2024 Jan 9;10(1):5. doi: 10.1038/s41421-023-00625-0. PMID: 38191529; PMCID: PMC10774422.
Metastatic Cancers
The study under analysis was a Phase I open-label, dose-escalation trial focused on Serplulimab, a novel anti-PD-1 antibody, in patients with advanced solid tumors (1). This antibody is characterized as a recombinant, humanized monoclonal antibody, which reportedly exhibits similar or enhanced affinity and antitumor activity compared to existing treatments like pembrolizumab and nivolumab.
The population targeted in this study comprised adult patients with histologically confirmed metastatic or recurrent solid tumors. These patients were specifically those who had either progressed on, or were intolerant to, or clinically unsuitable for standard treatments. The study design included the administration of Serplulimab in four escalating dose levels: 0.3, 1.0, 3.0, and 10.0 mg/kg, delivered intravenously every two weeks in 28-day cycles. The treatment duration was set for up to two years.
The main objectives of the study were to evaluate the safety and tolerability of Serplulimab, along with its preliminary efficacy. The primary endpoints identified were the incidence of treatment-emergent adverse events and determining the maximum tolerated dose of Serplulimab. As of the data cut-off on 27 July 2020, a total of 29 patients, all diagnosed with stage IV disease, had received one or more doses of Serplulimab. This cohort included a significant proportion of lung cancer patients (34.5%). Out of these, one patient (3.4%) had completed the treatment, while the majority, 26 patients (89.7%), had discontinued.
In terms of safety and tolerability, the study found that the maximum tolerated dose was not reached. Treatment-emergent adverse events were reported in 22 patients (75.9%), with nausea being the most common symptom (24.1%). There were no significant differences in the incidence of these events across the different dose cohorts. Notably, grade 3 or higher events occurred in four patients (13.8%). Additionally, pharmacokinetic data suggested minimal accumulation of Serplulimab after repeated administration, and functional programmed death 1 blockade was observed across all dose levels.
The preliminary efficacy results indicated an objective response rate of 8.0% and a disease control rate of 60.0%. Based on these findings, the study concluded that Serplulimab was generally well-tolerated and demonstrated potential antitumor activity, warranting further investigation in larger patient populations.
The study was registered on ClinicalTrials.gov with the identifier NCT03468751, dated 19 March 2018.
Reference
Ho CL, Chao TY, Chang CL, Lin HY. Safety, Tolerability, and Preliminary Efficacy of Serplulimab, a Novel Anti-PD-1 Antibody, in Patients with Metastatic or Recurrent Solid Tumors: A Phase I Study. BioDrugs. 2024 Jan 9. doi: 10.1007/s40259-023-00639-w. Epub ahead of print. PMID: 38194016.
Pediatric Cancers
The study, titled "Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF)," was a randomised, double-blind, phase 2b trial (1). It focused on long-term survivors of childhood cancer who were at risk for heart failure due to high-dose anthracycline exposure. The aim was to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in this population.
The population under investigation included patients who had a cancer diagnosis that resulted in at least 250 mg/m² cumulative exposure to anthracycline by age 21 years, had completed their cancer treatment at least 2 years prior, had an ejection fraction of at least 50% or fractional shortening of at least 25%, or both, and had a bodyweight of at least 40 kg. The study was conducted at 30 hospitals across the USA and Canada.
In terms of intervention, patients were randomly assigned in a 1:1 ratio to either carvedilol, which was up-titrated from 3.125 mg per day to 12.5 mg per day, or a placebo. This intervention was administered orally for 2 years. The control group in this study was the placebo group.
A total of 182 eligible participants were randomly assigned to either the carvedilol group (n=89) or the placebo group (n=93). The median age of participants was 24.7 years, with an even gender distribution and a majority of non-Hispanic White participants.
The primary endpoint of the study was to establish the effect of carvedilol on the left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). The results showed that LVWT/Dz was similar between the two groups, with a difference of 0.31 (95% CI -0.10 to 0.73; p=0.14) between the carvedilol and placebo groups. This indicates that there was no significant improvement in LVWT/Dz with carvedilol compared to placebo.
Safety was also assessed, revealing that two (2%) patients in the carvedilol group experienced adverse events of grade 2 or higher (one with shortness of breath and one with arthralgia), and there were no such events in the placebo group. There were no adverse events of grade 3 or higher, and no deaths were reported.
In conclusion, while low-dose carvedilol was found to be safe in long-term childhood cancer survivors at risk for heart failure, it did not result in a significant improvement in LVWT/Dz compared with placebo. Therefore, these results do not support the use of carvedilol for secondary heart failure prevention in this patient population. The study's follow-up duration, as of the data cutoff on June 10, 2022, had a median of 725 days. The study was funded by several organizations, including the National Cancer Institute and the Leukemia & Lymphoma Society.
Reference
Armenian SH, Hudson MM, Lindenfeld L, Chen S, Chow EJ, Colan S, Collier W, Su X, Marcus E, Echevarria M, Iukuridze A, Robison LL, Wong FL, Chen MH, Bhatia S. Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial. Lancet Oncol. 2024 Jan 9:S1470-2045(23)00637-X. doi: 10.1016/S1470-2045(23)00637-X. Epub ahead of print. PMID: 38215764.
Thoracic Cancers: Esophageal Squamous Cell Carcinoma
The SCALE-1 phase Ib clinical trial investigated the use of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC) (1). This single-arm study focused on the safety and efficacy of the combination treatment.
Participants in the trial were RLaESCC patients with clinical stages ranging from cT3-4aN0M0 to cT1-4aN+M0. The intervention under investigation involved administering neoadjuvant paclitaxel, carboplatin, and toripalimab every three weeks for two cycles. Additionally, short-course neoadjuvant radiotherapy was given between the doses of neoadjuvant immune-chemotherapy. Following the neoadjuvant treatment, esophagectomies were scheduled 4-6 weeks later.
The primary endpoint of the study was safety, with secondary endpoints including the pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Additionally, an exploratory biomarker analysis was conducted using gene expression profiles.
The trial enrolled 23 patients. All participants completed the neoadjuvant radiotherapy, and 21 finished the full neoadjuvant immune-chemotherapy doses and cycles. The most common grade 3/4 adverse events were neutropenia, leukopenia, and skin rash. Notably, there were no instances of grade 3 or higher esophagitis or pneumonitis. Of the 20 patients who underwent surgery, 11 achieved a pCR, translating to a 55% pCR rate. Two patients experienced grade IIIb surgical complications. At the time of the database lock, the study reported a 2-year PFS rate of 63.8% and a 2-year OS rate of 78%.
The tumor immune microenvironment analysis revealed that tumors achieving pCR had higher pretreatment T-cell-inflamed scores and demonstrated post-treatment reshaping of antitumor immunity. The study concluded that the combination of short-course neoadjuvant radiotherapy with chemotherapy and toripalimab was safe and showed promise in efficacy for patients with RLaESCC. The trial is registered under the number ChiCTR2100045104.
Reference
Jiang N, Zhang J, Guo Z, Wu Y, Zhao L, Kong C, Song X, Gu L, Zhao Y, Li S, He X, Ren B, Zhu X, Jiang M. Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial. J Immunother Cancer. 2024 Jan 9;12(1):e008229. doi: 10.1136/jitc-2023-008229. PMID: 38199609.