Immune System Diseases

All Conditions

Neoplasms

Blood and Lymph Conditions

Hypersensitivity

Hematologic Neoplasms

Hematologic Diseases

drug sensitivity testing of primary patient derived cancer cells

ex-vivo drug response assay

Sascha Dietrich, MD

This observational study evaluates if drug response testing can be performed within 7 days and analyzes the value of ex-vivo drug screening for hematological malignancies as a biomarker to predict outcome, clinical course and response to treatment.

Targeted treatments have revolutionized care of individual diseases. While a new generation of targeted drugs is emerging in leukemia and lymphoma it remains clinical reality that most genetic information is not used for therapeutic stratification. This is in part based on the shortcomings of traditional biomarker discovery within clinical trials, where throughput is limited in both, drug number and sample size. If it were possible to map the variable pathway dependencies and drug sensitivity patterns in individual patients it is likely to become an asset to identify genotype-phenotype associations, understand the underlying complexities of molecular networks and further precision medicine stratification.

To link clinical outcome and ex-vivo drug response assays, the investigators systematically measure pathway sensitivity and resistance of primary tumor cells ex-vivo using a diverse compound library for individual patients in need of treatment. By systematically analyzing ex-vivo drug response patterns, tumors should be functionally grouped, by response phenotype. While for the purpose of this study selection of a specific treatment will not be based on ex-vivo drug response assays, clinical response- and follow-up data of patients will be prospectively collected in parallel.

Blood samples, bonemarrow aspiration, tissue of lymphnodes

Systematic and Mechanism-based Approach to Rational Treatment Trials of Blood Cancer

Systematic and Mechanism-based Approach to Rational Treatment Trials of Blood Cancer (SMARTrial)

Patients' sample (blood, bonemarrow aspirate, tissue of lymphnode) will collected on day 0. Ex-vivo drug sensitivity testing will be performed.

Ex-vivo drug sensitivity categorizes drugs as sensitive/not sensitive. Results will be compared with clinical outcome of patient (response vs. stable disease as defined in the clinical response definition by protocol

prediction of time to next treatment by a mathematical model based on ex-vivo drug response testing

University Hospital Heidelberg

German Cancer Research Center

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Neoplasms, Second Primary

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

All Drugs and Chemicals

Antineoplastic Agents

Anti-Infective Agents

Androgens

Everolimus

Letrozole

Estrogens

Itraconazole

Bicalutamide

Hydroxyitraconazole

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Aromatase Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Cytochrome P-450 CYP3A Inhibitors

Androgen Antagonists

In case of an aberrantly active Estrogen Receptor (ER) pathway, patients will be treated with Letrozole 2.5mg daily orally until progression of disease.

In case of an aberrantly active androgen receptor (AR) pathway, patients will be treated with Bicalutamide 150mg daily orally until progression of disease.

In case of an aberrantly active phosphoinositide 3-kinase (PI3K) pathway, patients will be treated with Everolimus 10mg daily orally until progression of disease.

In case of an aberrantly active Hedgehog (HH) or PI3K pathway, patients will be treated with Itraconazole 300mg twice daily orally until progression of disease.

Letrozole 2.5mg tablet - 2.5mg once dailty until progression of disease.

Letrozole Oral Product

Bicalutatmide 150mg tablet - 150mg once daily until progression of disease.

Bicalutamide Oral Product

Everolimus 10mg tablet - 10mg once daily until progression of disease.

Everolimus Oral Product

Itraconazole 100mg capsule - 300mg twice daily until progression of disease.

Itraconazole Oral Product

Jurgen M Piek, MD, PhD

Ruud Bekkers, MD, PhD

Jurgen M Piek, MD. PhD.

A.M.J. Thijs, MD, PhD

L Massuger, Prof

N. Ottevanger, Prof

H.M. Westgeest, MD, PhD

H.P.M. Smedts

Sandrina Lambrechts, MD,PhD

I Boere, MD., PhD.

M.C. Vos, MD, PhD

The purpose of this prospective, parallel-group, cohort study is to implement phenotype-guided targeted therapy based on functional signal transduction pathway (STP) activity in recurrent ovarian cancer patients using a novel mRNA-based assay. Existing targeted drugs with tolerable toxicity profiles are used to investigate the therapeutic value beyond their approved indication, which are deemed beneficial in the select group of patients with a relevant predominantly active functional STP, in order to improve survival and maintain quality of life.

Rationale: Ovarian cancer is one of the most lethal cancers in the world. Standard therapy consists of debulking surgery and chemotherapy. However, despite this aggressive treatment, recurrent disease almost invariably occurs resulting in a five-year survival rate of approximately 30%. Tumour growth is driven by several signal transduction pathways (STPs), and twelve major STPs have been identified as important for carcinogenesis. Currently, several targeted therapy drugs are available and new targeted drugs are being developed. With a newly developed technique, Signal Transduction Activation (STA) analysis, it is possible to assess which pathway is predominant in a specific (ovarian) cancer sample. Therefore, we hypothesize that specifically targeting the predominant STP might impair tumour growth and improve survival.

Objective: This study aims to investigate the progression-free survival (PFS) according to RECIST 1.1 criteria on matched targeted therapy by STA-analysis (PFS2) in comparison to the PFS recorded on the therapy administered immediately prior to enrolment (PFS1) in women with recurrent ovarian cancer.

Study design: A multi-centre prospective, parallel-group, cohort study. Study population: Recurrent ovarian cancer patients with platinum-resistant disease, patients who refrain from standard therapy and patients who are not yet eligible for standard palliative chemotherapy, including all histological subtypes.

Intervention: STA-analysis will be performed on a biopsy taken from the recurrent tumour. Patients will be included if a predominant pathway is identified for which a matched targeted drug is available and deemed adequate by the multidisciplinary tumour board. We will start with targeted therapy in patients with oestrogen receptor, androgen receptor, phosphoinositide 3-kinase and Hedgehog pathway active tumours, since targeted therapy interceding these pathways are easily available with tolerable side effects.

Main study parameters/endpoints: The primary outcome is therapy response defined as PFS2/PFS1 ratio according to RECIST 1.1 criteria. Secondary outcomes include the proportion of patients with an actionable active pathway and the proportion of patients receiving matched targeted therapy, best overall response (according to RECIST 1.1 criteria), one-year survival, overall survival, predictive value of STA-analysis results, side effects, quality of life, cost-effectiveness and change in STP activity score comparing the score before treatment and after disease progression.

Targeted therapy based on functional signal transduction pathway activation in patients with recurrent ovarian cancer.

Signal TrAnsduction Pathway Activity Analysis in OVarian cancER

PFS on matched targeted therapy (PFS2) is defined as the time from start of matched targeted therapy to disease progression, defined by RECIST 1.1 criteria, or death from any cause. PFS on prior therapy (PFS1) is defined as the time from start of the prior treatment to disease progression defined by RECIST 1.1 criteria

Proportion of patients included in arm A, B, C, D.

One-year survival is defined as the time from start matched targeted therapy till death or the end of the one-year follow-up period.

Defined as the time from start matched targeted therapy till death.

Assessed according to the PRO-CTCAE and NCI CTCAE 5.0

HRQoL is assessed using standardized questionnaires from the EORTC QLQ-C30 and QLQ-OV28.

Standardized EuroQol 5D (EQ-5D-5L) questionnaire is used to calculated the cost-effectiveness.

If pathway activity scores are available from a second (voluntary) biopsy for after treatment has ended and before standard (palliative) treatment has started, change in pathway scores are assessed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Systematic and Mechanism-based Approach to Rational Treatment Trials of Blood Cancer	NCT03488641	Hematologic Dis... Treatment	ex-vivo drug re...	18 Years -	German Cancer Research Center
Signal TrAnsduction Pathway Activity Analysis in OVarian cancER	NCT03458221	Recurrent Ovari... Signal Transduc... Therapy-Associa...	Letrozole Oral ... Bicalutamide Or... Everolimus Oral... Itraconazole Or...	18 Years -	Gynaecologisch Oncologisch Centrum Zuid
Systematic and Mechanism-based Approach to Rational Treatment Trials of Blood Cancer	NCT03488641	Hematologic Dis... Treatment	ex-vivo drug re...	18 Years -	German Cancer Research Center

Spots Global Cancer Trial Database for signal transduction pathway deregulation