Multi-analyte interrogation based treatment of advanced refractory cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15624-e15624
Author(s):  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Darshana Patil ◽  
Anantbhushan Ranade ◽  
Amit Bhatt ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Response To Treatment ◽  
Patient Specific ◽  
Solid Organ ◽  
Systemic Treatments

e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (precision medicine) in such populations were largely based on a single-indication-single-drug paradigm which had limited application. We hypothesized that advanced refractory malignancies have latent vulnerabilities which can be identified by an integrational multi-analyte interrogation of the tumor, and can be targeted using patient-specific combination regimens to yield clinical benefit. Methods: Fresh tumor tissue and blood samples were obtained from 158 patients with solid organ cancers where the disease had progressed following failure of at least two lines of standard of care systemic treatment options. These samples were used for Encyclopedic Tumor Analysis (ETA) which interrogated gene mutations, gene overexpression, pathway dysregulation, immunohistochemistry as well as in vitro chemosensitivity profiling of viable tumor cells. Integration of datasets from the multi-analyte ETA was used to generate patient-specific therapy recommendations. Patients who received ETA-guided treatments were followed up and response to treatment was retrospectively evaluated from radiological scans. Results: All patients received ETA-guided individualized treatments which were combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Complete or Partial Response (CR or PR) was observed in 76 patients yielding an Objective Response Rate (ORR) of 48.1%. 67 patients showed Stable Disease (SD), thus yielding a Disease Control Rate (DCR) of 90.5%. Median Progression Free Survival (PFS) was 117 days (Range 27 – 379 days). There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: Viable efficacious combination treatment options can be made available for patients with advanced refractory malignancies via ETA, despite perceived non-availability or non-viability of standard of care treatment options.

scholarly journals Clinical efficacy of combination therapies with androgen receptor antagonists for treatment of multiple refractory cancers.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 115-115
Author(s):  
Dadasaheb B Akolkar ◽  
Darshana Patil ◽  
Vineet Datta ◽  
Ajay Srinivasan ◽  
Rajan Datar
Keyword(s):  
Androgen Receptor ◽  
Treatment Response ◽  
Clinical Benefit ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Disease Status ◽  
Solid Organ ◽  
Combination Treatments

115 Background: Androgen Receptor (AR) antagonists have been the mainstay of prostate cancer treatments. However, there is increasing interest in the use of anti-AR agents in treatment of other cancers such as Triple Negative Breast Cancer and Lung Cancer. AR antagonists are usually administered as single agents and rarely in combination with other cytotoxic or targeted agents. We hypothesized that administration of AR antagonists indicated by Encyclopedic Tumor Analysis (ETA) in synergistic combination with cytotoxic, targeted or other endocrine agents may afford clinical benefit for refractory cancers. Methods: We evaluated treatment response in a basket of 18 patients with various advanced refractory solid organ malignancies, who received personalized treatments based on ETA investigations. As part of ETA, freshly biopsied tumor tissue and blood samples were evaluated for various markers such as gene mutations (DNA), gene expression (RNA) and receptor proteins (immunohistochemistry). Finally, viable tumor cells from the freshly biopsied tissue were used in in vitro chemosensitivity analysis with a panel of cytotoxic and targeted therapy agents. Radiological disease status was evaluated retrospectively and treatment response as well as Progression Free Survival (PFS) was determined. Results: Among the 18 patients, there were 8 males (44%) and 10 females (56%) with median age of 58 years (range 28 – 79). Patients had received a median of 3 prior lines of treatment (range 1 – 14). All 18 patients received ETA guided combination treatments which included an AR blockade. 9 patients showed Partial Response ( PR) with an Objective Response Rate (ORR) of 50%. 5 patients (28%) showed stable disease for ≥3 months (Clinical Benefit Rate = 77.8%), while 4 patients (22%) showed disease progression. In 2 patients (11%) disease progressed at ~60 days and in the remaining 2 patients (11%) progression was seen at > 120 days. Treatments were well tolerated without severe adverse events. Conclusions: Androgen addicted, refractory solid organ tumors respond to combinations of cytotoxic, targeted and endocrine agents along with AR antagonists guided by ETA.

scholarly journals Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers

2021 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Rajnish Nagarkar ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Objective Response ◽  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Cytotoxic Agents ◽  
Patient Specific ◽  
Solid Organ ◽  
Specific Combination ◽  
Anticancer Treatment ◽  
Combination Regimens

Abstract Background Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses. Methods We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Results Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow, up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths. Conclusions ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. LIQUID IMPACT ID CTRI/2019/02/017548.

scholarly journals CMET-37. CLINICAL UTILITY OF ENCYCLOPEDIC TUMOR ANALYSIS TO TREAT PATIENTS WITH BRAIN METASTASIS IN REFRACTORY CANCERS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi59-vi60
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Dadasaheb Akolkar ◽  
Anantbhushan Ranade ◽  
Amit Bhatt ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Treatment Options ◽  
Brain Mri ◽  
Gene Mutations ◽  
Solid Organ ◽  
Pet Ct ◽  
The Impact

Abstract Brain metastasis in solid organ cancers is associated with adverse prognosis, which is further aggravated by limited systemic treatment options. Such patients are also often excluded from clinical trials since their poor prognosis is perceived to unfavorably impact trial outcomes and misrepresent efficacy data. We retrospectively evaluated the efficacy of treatment guided by Encyclopedic Tumor Analysis (ETA) in patients with advanced refractory malignancies and brain metastases to determine the impact on outcomes. Freshly biopsied tumor tissue (primary / lymph node / liver) and peripheral blood of patients were used for integrational multi-analyte investigations as part of ETA, which included gene mutations, gene expression, and in vitro chemosensitivity profiling of viable tumor cells. Based on ETA, patients received individualized therapy recommendations. All patients underwent a PET-CT scan as well as MRI scan prior to treatment start to determine extent of disease. All patients underwent follow-up PET-CT scans and brain MRI scans every 6–8 weeks. Of the ten patients with brain metastases, which were evaluated after receiving ETA-guided treatment, the median follow-up duration was 97 days (range 79 – 180 days) during which all ten patients remained progression-free. Median time to progression for these patients on the last (failed) line of treatment was 91 days (range 30 - 176 days). Five patients showed partial response and five patients showed stable disease while on ETA-guided treatment. During the follow-up period, all brain metastases were either stable (n=7) or had regressed (n=3), and none of the patients reported new brain lesions. Personalized ETA guided treatments imparted clinical benefit by halting disease progression in this cohort of high-risk patients who would have otherwise been considered for palliative regimens due to perceived unfavorable prognosis.

DNA damage response (DDR) gene mutations (mut), mut load, and sensitivity to chemotherapy plus immune checkpoint blockade in urothelial cancer (UC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 300-300 ◽  
Author(s):  
Matt D. Galsky ◽  
Andrew V. Uzilov ◽  
Russell Bailey McBride ◽  
Huan Wang ◽  
Vaibhav G. Patel ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Immune Checkpoint ◽  
Predictive Value ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Response To Treatment ◽  
Cd8 Cells

300 Background: Somatic mut in DDR genes have been associated with increased sensitivity to cisplatin in UC. Higher mut load has correlated with response to immune checkpoint blockade. We hypothesized that DDR mut result in higher mut load and DDR mut UC may be particularly sensitive to both chemotherapy and immune checkpoint blockade. Methods: Three cohorts were utilized: (1) TCGA UC cohort (n = 389), (2) Mount Sinai (MS) cohort (n = 67) of UC (cystectomy) specimens subjected to targeted exome sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab (GCI) in metastatic UC from which 28/36 enrolled patients (pts) had specimens suitable for whole exome sequencing. DDR mut were defined as somatic alterations in one of 52 genes. Deleterious (del) mut were defined as nonsense, frameshift, splice site, or hotspot point mut. Results: The mut load using all genes in the TCGA cohort, and restricted to the 341 IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between del DDR mut and mut load are shown (Table). In the MS cohort, CD8+cells/mm2 by IHC were higher in tumors with del DDR mut versus no DDR mut (p = 0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative predictive value of a del DDR mut for objective response to treatment was 40.9% (95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 12.6-56.6%), respectively. Median progression-free survival in the GCI cohort was 308 days (95% CI 270-NR) in del DDR mut and 196 days (95% CI 185-372) in others (p = 0.24). Notably, 2/9 pts with del DDR mutations, and with the highest mut loads, achieved complete responses after GCI and are alive without evidence of disease at 2.1+ and 1.8+ years. Conclusions: DDR mut are associated with higher mut load in UC, a high likelihood of response to GCI, and may identify a subset of pts achieving durable disease control. GC plus PD-1/PD-L1 blockade should be explored in DDR mut UC. Clinical trial information: NCT01524991. [Table: see text]

scholarly journals Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
Sewanti Limaye ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Outcomes ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Patient Specific ◽  
Solid Organ ◽  
Free Survival ◽  
Combination Regimens

Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation (ETA: Encyclopedic Tumor Analysis) yields significant treatment response and survival benefits in advanced or refractory solid organ cancers.Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy naïve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS).Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths.Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers.Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548.

scholarly journals Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592090604 ◽  
Author(s):  
Catherine Knowlson ◽  
Paula Haddock ◽  
Victoria Bingham ◽  
Stephen McQuaid ◽  
Paul B. Mullan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Response To Treatment ◽  
Increased Sensitivity

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment.

scholarly journals Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers

2021 ◽  
Vol 1 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Rajnish Nagarkar ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Objective Response ◽  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Cytotoxic Agents ◽  
Patient Specific ◽  
Solid Organ ◽  
Specific Combination ◽  
Anticancer Treatment ◽  
Combination Regimens

Background: Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses.Methods: We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS).Results: Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow-up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths.Conclusion: ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011,808. LIQUID IMPACT ID CTRI/2019/02/017,548.

scholarly journals Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002057
Author(s):  
Yousef Zakharia ◽  
Robert R McWilliams ◽  
Olivier Rixe ◽  
Joseph Drabick ◽  
Montaser F Shaheen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Programmed Death ◽  
Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Endometriumkarzinom: Kombination aus Lenvatinib und Pembrolizumab zeigt Wirksamkeit unabhängig vom Mikrosatellitenstatus

2021 ◽  
pp. 1-2
Author(s):  
Sarah Matz
Keyword(s):  
Endometrial Carcinoma ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Efficacy Analysis ◽  
Duration Of Response ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Prior Systemic Therapy ◽  
Grade 3

<b>Purpose:</b> Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. <b>Methods:</b> Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. <b>Results:</b> At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. <b>Conclusion:</b> Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile. <b>Trial registration:</b> ClinicalTrials.gov NCT02501096.

Functional precision medicine in colorectal cancer based on patient-derived tumoroids and in-vitro sensitivity drug testing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15567-e15567
Author(s):  
Lars Henrik Jensen ◽  
Anders Kristian Moeller Jakobsen ◽  
Birgitte Mayland Havelund ◽  
Cecilie Abildgaard ◽  
Chris Vagn-Hansen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Primary Endpoint ◽  
Drug Testing ◽  
Progression Free Survival ◽  
Patient Specific ◽  
Precision Oncology ◽  
Sensitivity Testing ◽  
In Vitro Sensitivity

e15567 Background: Precision oncology based on in-vitro, functional assays has potential advantages compared to the much more common molecular approach, but the clinical benefit is unknown. We here report the results from the largest prospective interventional clinical trial testing the clinical outcome in colorectal cancer patients treated with drugs showing cytotoxic effect in matched patient-derived tumoroids. Methods: This single-center, phase II trial included patients with metastatic colorectal cancer previously exposed to all standard therapies. Specimens from one to three 18-16 G core needle biopsies were manually dissected, enzymatically treated, cultivated, and incubated to form 3D spherical microtumors, i.e. tumoroids. In the assay for in-vitro sensitivity testing, the tumoroids were challenged with single drugs and combinations thereof to determine patient-specific responses. Using tumoroid screening technology (IndiTreat, 2cureX, Copenhagen, Denmark), results were generated by comparing the sensitivity of the individual patient’s tumoroids with a reference panel from other patients. The testing included standard cytostatics and drugs with proven effect in previous early-phase clinical trials, a total of 15 drugs. The primary endpoint was the fraction of patients with progression-free survival (PFS) at two months. Based on placebo arms in randomized last-line trials, a minimal relevant difference of 20% (20% to 40%) was stated. Using Simon's two-stage design, a sample size of 45 patients was calculated with at least 14 PFS at two months (significance 5%, power 90%). Results: Ninety patients were enrolled from 9/2017 to 9/2020. Biopsies from 82 patients were obtained and sent for tumoroid formation of which 44 (54%, 95% CI 42-65) were successful and at least one treatment was suggested. Thirty-four patients initiated treatment according to the response obtained in the drug assays within a median of 51 days from inclusion (IQR 39-63). The primary endpoint, PFS at two months, was met in 17 of 34 patients (50%, 95%CI 32-68). There were no radiological responses. Median PFS was 81 days (95% CI 51-112) and median OS was 189 days (95% CI 103-277). Conclusions: Precision oncology using a functional approach with patient-derived tumoroids and in-vitro drug sensitivity testing seems feasible. The approach is limited by the fraction of patients with successful tumoroid development. The primary endpoint was met, as half of the patients were without progression at two months. Further clinical studies are justified. Clinical trial information: NCT03251612.

Sign in / Sign up

Export Citation Format

Share Document