Decisional Conflict after Deciding on Potential Participation in Early Phase Clinical Cancer Trials:Dependent on Global Health Status, Satisfaction with Communication, and Timing

SIMPLE SUMMARY: Early phase clinical trials are an essential part of modern drug development and thus the advance of anti-cancer therapies for patients. However, deciding whether to participate in such trials can be complex and patients have reported decisional conflict (i.e., unresolved decisional needs). The aim of our study was to untangle several factors that contribute to decisional conflict in patients with advanced cancer who have recently been asked to decide whether to participate in early phase clinical trials. We found that patients experienced less decisional conflict if they had a better global health status, higher satisfaction, and made their decision sooner. Other factors, such as the decision to (not) participate, did not prove to be the best indicators for decisional conflict. With these insights, we can start to build hypotheses on how to improve the decision-making process for patients with end-stage cancer, which can ultimately improve their quality of life. ABSTRACT: When standard treatment options are not available anymore, patients with advanced cancer may participate in early phase clinical trials. Improving this complex decision-making process may improve their quality of life. Therefore, this prospective multicenter study with questionnaires untangles several contributing factors to decisional conflict (which reflects the quality of decision-making) in patients with advanced cancer who recently decided upon early phase clinical trial participation (phase I or I/II). We hypothesized that health-related quality of life, health literacy, sense of hope, satisfaction with the consultation, timing of the decision, and the decision explain decisional conflict. Mean decisional conflict in 116 patients was 30.0 (SD = 16.9). Multivariate regression analysis showed that less decisional conflict was reported by patients with better global health status (β = −0.185, p = 0.018), higher satisfaction (β = −0.246, p = 0.002), and who made the decision before (β = −0.543, p < 0.001) or within a week after the consultation (β = −0.427, p < 0.001). These variables explained 37% of the variance in decisional conflict. Healthcare professionals should realize that patients with lower global health status and who need more time to decide may require additional support. Although altering such patient intrinsic characteristics is difficult, oncologists can impact the satisfaction with the consultation. Future research should verify whether effective patient-centered communication could prevent decisional conflict

Tisotumab Vedotin in Combination with Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer:Results from the innovaTV 205/GOG-3024/ENGOT-cx8 Study

PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E).CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.</p

Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer

Conditional Inactivation of HIF-1 Using Intrabodies

Hypoxia is a hallmark of solid cancers and triggers the transcription of genes responsible for cell survival. The transcription factor Hypoxia-Inducible Factor 1 (HIF-1) is a key regulator in this response and frequently activated in human cancer. HIF-1 activation is associated with tumor aggressiveness and poor clinical outcome and, therefore, may provide an attractive therapeutic target. Here we provide a novel approach for HIF-1 targeted therapy using single-domain llama antibodies directed against the HIF-1α oxygen dependent degradation domain which encompass the N-terminal transactivation domain. Conditional expression of HIF intrabodies in mammalian cells interfered with binding to pVHL and inhibited hypoxia induced activation of endogenous target genes. Inducible intrabody targeting is a highly specific strategy for temporal protein inactivation and may have applications for disease treatment

Cancer Therapy-Related Cardiac Dysfunction of Nonanthracycline Chemotherapeutics. What Is the Evidence?

Cancer therapy–related cardiac dysfunction (CTRCD) is one of the most concerning cardiovascular side effects of cancer treatment. Important reviews within the field of cardio-oncology have described various agents to be associated with a high risk of CTRCD, including mitomycin C, ifosfamide, vincristine, cyclophosphamide, and clofarabine. The aim of this study was to provide insight into the data on which these incidence rates are based. We observed that the reported cardiotoxicity of mitomycin C and ifosfamide is based on studies in which most patients received anthracyclines, complicating the interpretation of their association with CTRCD. The high incidence of vincristine-induced cardiotoxicity is based on an incorrect interpretation of a single study. Incidence rates of clofarabine remain uncertain due to a lack of cardiac screening in clinical trials. The administration of high-dose cyclophosphamide (>1.5 g/m2/day) is associated with a high incidence of CTRCD. Based on our findings, a critical re-evaluation of the cardiotoxicity of these agents is warranted

Efficient target-selected mutagenesis in Caenorhabditis elegans: Toward a knockout for every gene

Reverse genetic or gene-driven knockout approaches have contributed significantly to the success of model organisms for fundamental and biomedical research. Although various technologies are available for C. elegans, none of them scale very well for genome-wide application. To address this, we implemented a target-selected knockout approach that is based on random chemical mutagenesis and detection of single nucleotide mutations in genes of interest using high-throughput resequencing. A clonal library of 6144 EMS-mutagenized worms was established and screened, resulting in the identification of 1044 induced mutations in 109 Mbp, which translates into an average spacing between exonic mutations in the library of only 17 bp. We covered 25% of the open reading frames of 32 genes and identified one or more inactivating mutations (nonsense or splice site) in 84% of them. Extrapolation of our results indicates that nonsense mutations for >90% of all C. elegans genes are present in the library. To identify all of these mutations, one only needs to inspect those positions that—given the known specificity of the mutagen—can result in the introduction of a stop codon. We define these positions as nonsense introducing mutations (NIMs). The genome-wide collection of possible NIMs can be calculated for any organism with a sequenced genome and reduces the screening complexity by 200- to 2000-fold, depending on the organism and mutagen. For EMS-mutagenized C. elegans, there are only ∼500,000 NIMs. We show that a NIM genotyping approach employing high-density microarrays can, in principle, be used for the genome-wide identification of C. elegans knockouts

Abstract CT207: A phase 1 open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a Trispecific Humabody® T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA)

Humabodies* are fully human VH antibody components that can be connected by short peptide linkers to make multi-specific therapeutics. CB307 is a tri-specific Humabody targeting prostate specific membrane antigen (PSMA/FOLH1), CD137 (4-1BB/TNFSF9) and human serum albumin (HSA). Unlike CD3 targeting bispecific compounds, stimulation of CD137 on T cells can promote T cell cytotoxicity, proliferation, survival and memory T cell formation without compromising safety, including cytokine release syndrome (CRS). In addition, HSA binding assists CB307 penetration into the tumor since albumin is enriched in the tumor microenvironment. Several cancers including prostate cancer and lung cancer are known to have PSMA expression. The objectives of the POTENTIA study are to determine the maximum tolerated dose (MTD) and pharmacokinetics of CB307 and to assess preliminary anti-tumor activity in patients with PSMA+ solid tumor.Methods: The phase 1 study consists of dose escalation (part 1) and cohort expansion (part 2) components, and the study is currently enrolling patients in part 1 without dose limiting toxicities (DLTs). The dose escalation uses an accelerated titration design (ATD) and a modified continual reassessment method (mCRM) to guide the MTD and the recommended phase 2 dose (RP2D). The key inclusion criteria are as follows: histologically confirmed advanced or metastatic PSMA expressing solid tumors determined by immunohistochemistry; not amenable to standard-of-care; RECIST measurable disease or increased serum PSA at baseline (for bone metastasis-only prostate cancer). The key exclusion criteria are patients with brain metastases; patients who have discontinued previous immunotherapy due to intolerable immune-related adverse events; patients with acute infections or autoimmune diseases. Cohort expansion uses the same eligibility criteria, however, at least 3 patients with castration-resistant prostate cancer harboring either BRCA1, BRCA2, ATM and/or CDK12 mutation(s) will be enrolled. CB307 is administered intravenously every week. PSMA-PET scan and tumor biopsy are taken to understand the mechanism of action of CB307 as well as a change of PSMA expression during CB307 treatment. NCT04839991 * “Humabody” is a registered trademark ® of Crescendo Biologics Ltd.Citation Format: Johann S. de Bono, Hendrik-Tobias Arkenau, Eelke H. Gort, Lot L. Devriese, Elisa Fontana, Daan G. Knapen, Crescens Tiu, Anja Williams, Derk Jan A. de Groot, Ulug M. Gunaydin, Phillip Bartlett, Andrew J. Pierce, Philip Bland-Ward, Kenji Hashimoto, E.G. Elisabeth de Vries. A phase 1 open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a Trispecific Humabody® T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12Suppl):Abstract nr CT207

Additional file 1 of Patient values in patient-provider communication about participation in early phase clinical cancer trials: a qualitative analysis before and after implementation of an online value clarification tool intervention

Additional file1: Supplementary table 1. Final codebook (i.e. additions and changes to the initial codebook are italicized)

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.</p