Neoplasms

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Pancreatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma, Endometrioid

Endocrine System Diseases

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

Gonadal Disorders

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endometrial Neoplasms

Uterine Neoplasms

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Natriuretic Agents

All Drugs and Chemicals

Mannitol

Escalating doses of VS-6766 (RO5126766) and Defactinib (VS-6063) were evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation followed a 3+3 design with a maximum of four patient cohorts.

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients advanced RAS mutant solid tumours with biopsiable disease (6 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with LGSOC (20 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with CRC (10 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS G12V mutant NSCLC (10 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) (10 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with pancreatic cancer (10 patients).

VS-6766 will be supplied as 0.8mg hypromellose (HPMC) capsules for oral administration. The capsule fill consists of VS-6766 and the inactive ingredients mannitol and magnesium stearate.

VS-6766 will be administered on a twice weekly (Monday and Thursday or Tuesday and Friday) schedule for 3 weeks followed by 1 week off in every 4 week cycle, under fasting conditions (approximately 1 hour prior or 2 hours after a meal). The starting dose, based on the previous Phase I trial will be 3.2 mg given orally as a single daily dose. This can be escalated to a maximum of 4mg (as per dose escalation rules in the protocol).

VS-6766

Defactinib is formulated as a white to off-white oval tablet for oral administration and supplied in single unit dose strength of 200 mg in 120 cc (HDPE) bottles. In addition to Defactinib, formulation components include microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and magnesium stearate.

Patients will receive Defactinib orally immediately after a meal twice daily (approximately every 12 hours) for 3 weeks followed by 1 week off in every 4 week cycle. The starting dose will be 200mg. This can be escalated to a maximum of 400mg (as per dose escalation rules in the protocol).

Defactinib

Udai Banerji, FRCP, PhD

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib (VS-6063), and the dual RAF/MEK inhibitor, VS-6766 (RO5126766) in patients with advanced solid tumours. VS-6766 (RO5126766) is the same compound as CH5126766.

There are two parts to this study, the dose escalation phase and the dose expansion phase. In the dose escalation phase, cohorts of 3 to 6 patients will be enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). This will be followed by a dose expansion phase to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib, and the dual RAF/MEK inhibitor, VS-6766 in patients with advanced solid tumours.

There are two parts to this study, the dose escalation phase and the dose expansion phase. In the dose escalation phase, cohorts of 3 to 6 patients were enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Up to 24 patients with solid tumours were treated in the dose escalation phase of this study.

The dose escalation phase is now closed to recruitment.

This will be followed by a dose expansion phase of 86 patients to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

The dose expansion phase is made up of 7 cohorts:

* 20 patients with KRAS mutant non-small-cell lung cancer (NSCLC);
* 7 patients with solid tumours (enriched for those with RAS mutations) willing to undergo biopsies at three time points throughout the study;
* 20 patients with low grade serous ovarian cancer (LGSOC);
* 10 patients with colorectal cancer (CRC);
* 10 patients with KRAS G12V mutant NSCLC;
* 10 patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis related) and
* 10 patients with pancreatic cancer.

The following cohorts are still open to recruitment:

* Patients with low grade serous ovarian cancer (LGSOC);
* Patients with KRAS G12V mutant NSCLC;
* Patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) and
* Patients with pancreatic cancer.

Patients will take the two investigational medicinal products (IMPs) as follows:

VS-6766 will be administered orally twice a week on Monday/Thursday or Tuesday/Friday at least one hour prior or two hours after a meal. The starting dose of VS-6766 will be 3.2mg once a day, twice a week and can be escalated to a maximum of 4mg once a day, twice a week.

Defactinib will be administered orally twice a day immediately after a meal. The starting dose of Defactinib will be 200mg twice daily and can be escalated to a maximum of 400mg twice daily.

A cycle length is 4 weeks (28 days). Combination dosing (VS-6766 and Defactinib) will commence on Cycle 1 Day 1 for 3 weeks followed by one week without either drug in week 4 (i.e. 3 weeks on, 1 week off).

For patients consenting to optional biopsies, a run-in dose of VS-6766 will be administered on a single day anywhere between Days -7 to Day -3 in order to facilitate pharmacodynamic (PD) biomarker analysis. Therefore, for patients undergoing biopsies the first cycle will be 5 weeks long and subsequent cycles will consist of 4 weeks.

If this schedule is not tolerated, alternative schedules may be explored following discussion by the Safety Review Committee.

The dose escalation phase will enrol patients with advanced RAS mutant solid tumours.

In the dose expansion phase, patients are assigned to one of the following cohorts based on their diagnosis:

* KRAS mutant NSCLC cohort
* LGSOC cohort
* RAS mutant CRC cohort
* Advanced RAS mutant solid tumour cohort - patients in this cohort must have biopsiable disease, be willing and consent to undergo biopsies at three time-points.
* KRAS G12V mutant NSCLC cohort
* RAS/RAF mutant endometrioid cohort
* Pancreatic cohort

Non-randomised: Participants are expressly assigned by phase of study and diagnosis.

Phase I Trial of Defactinib and VS-6766.

FRAME: A Phase I Trial of the Combination of Defactinib (VS-6063) (FAK Inhibitor) and VS-6766 (RO5126766) (CH5126776) (a Dual RAF/MEK Inhibitor) in Patients With Advanced Solid Tumours

Determination of disease response by RECIST criteria version 1.1 and collection of data related to progression free survival.

Quantification of biomarkers such as p-MEK, p-ERK and p-FAK, E-cadherin and vimentin and enumeration of T cell populations which express CD8, CD4 and CD25.

Correlation of antitumour activity of the combination of VS-6766 and Defactinib with the detection of putative predictive biomarkers of response and resistance in archival tumours and plasma DNA.

To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT) as specified in the protocol.

To assess the safety and toxicity profile of VS-6766 and Defactinib. To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Determination of the PK parameter Cmax of VS-6766 and Defactinib when dosed together.

Determination of the PK parameter terminal half-life of VS-6766 and Defactinib when dosed together.

Determination of the PK parameter area under the curve of VS-6766 and Defactinib when dosed together.

Verastem, Inc.

Institute of Cancer Research, United Kingdom

Endometriosis

Adenocarcinoma, Clear Cell

Adenomyoepithelioma

Endocrine Gland Neoplasms

Epithelial-myoepithelial Carcinoma

Ellen Obermann, MD, Dr.

Ellen C Obermann, MD

The purpose of this study is to determine whether a relationship exists between a previously established diagnosis of endometriosis and the consecutive risk of developing a clear cell or endometrioid ovarian carcinoma. All histopathological records since 1980 with these diagnoses (endometriosis, clear cell and endometrioid ovarian carcinoma) will be reviewed. Cancer registry data will be assessed to investigate differences in survival of women with endometriosis-associated ovarian carcinomas and those ovarian carcinoma patients without previous diagnosis of endometriosis.

Endometriosis and Frequency of Endometriosis-associated Ovarian Carcinomas (EAOC)

Endometriosis and Frequency of Endometriosis-associated Ovarian Carcinomas (EAOC) - Epidemiological and Molecular Pathological Aspects

University Hospital, Basel, Switzerland

Immune System Diseases

Hypersensitivity

Cystadenocarcinoma, Serous

Fallopian Tube Neoplasms

Cystadenocarcinoma

Fallopian Tube Diseases

Neoplasms, Cystic, Mucinous, and Serous

Fallopian Tube Cancer

Adenocarcinoma of the Appendix

Antineoplastic Agents

Carboplatin

Arm 1 (Standard Dosing): Carboplatin AUC5 based on nuclear medicine renal clearance.

Arm 2 (Adaptive Therapy): Carboplatin dose will be calculated according to the CA125 value.

Treatment in both arms will be administered intravenously (IV) every 21 days (q21D) and for a maximum of 6 cycles in Arm 1 and 12 cycles in Arm 2.

ACTOv Trial Coordinator

Michelle Lockley

ACTOv will compare standard 3-weekly carboplatin (AUC5), to carboplatin delivered according to an AT regimen. The AT regimen will modify carboplatin dose according to changes in the clinical-standard serum biomarker CA125 as a proxy measure of total tumour burden and an individual patient's response to the most recent chemotherapy treatment. AT could prolong sensitivity to carboplatin and extend tumour control, while simultaneously reducing chemotherapy dose and drug-induced toxicity. Carboplatin is a low cost and low toxicity drug that has an enduring and central role in ovarian cancer treatment.

Adaptive ChemoTherapy for Ovarian Cancer in Patients With Replased Platinum-sensitive High Grade Serous or High Grade Endometrioid Ovarian Cancer

A Multicentre Phase II Randomised Controlled Trial to Evaluate the Efficacy of Adaptive Therapy (AT) With Carboplatin, Based on Changes in CA125, in Patients With Relapsed Platinum-sensitive High Grade Serous or High Grade Endometrioid Ovarian Cancer

Measured from the date of randomisation to the date of objective progression (investigator assessed using RECIST v1.1) but comparing CT scans to the baseline CT rather than the radiological nadir), clinical progression or death from any cause (in the absence of progression)

the number of eligible patients approached who accept randomisation and continue to receive treatment

the proportion of eligible patients approached who accept randomisation and continue to receive treatment

the number of treatment cycles that are delivered as per protocol, described by trial arm

the proportion of treatment cycles that are delivered as per protocol, described by trial arm

total cumulative carboplatin dose will be calculated for each patient over time on treatment, and described by trial arm

adverse events will be categorised using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5. The number of patients who suffer a grade 3 or 4 toxicity at any time, and the maximum grade of toxicity for each adverse event term, will be described by trial arm

adverse events will be categorised using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5. The percentage of patients who suffer a grade 3 or 4 toxicity at any time, and the maximum grade of toxicity for each adverse event term, will be described by trial arm

measured using European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC questionnaires): Quality of Life cancer 30 (QLQ-C30) (suitable for all cancer types) and Qualify of life questionnaire (QLQ-OV28 (ovarian cancer-specific)) in scale of 4 (1 is not very much and 4 very much)

measured using European Quality of life questionnaire five dimensions (EQ-5D (descriptive profile of health state)) in scale of 5 (1 is no problem and 5 is extreme problem)

measured using Fear of progression questionnaire (FOP-Q SF) in scale of 1 to 5 where 1 is never and 5 is very often

measured at baseline, 3-weekly during treatment, 6-weekly during surveillance and 12-weekly during follow-up

of patients who progress will be described by trial arm including the time-to-next treatment (measured from randomisation)

of patients who progress will be described by trial arm including the time treatment received (measured from randomisation)

of patients who progress will be described by trial arm including the time response to this treatment (measured from randomisation)

measured from the date of randomisation to the date of death from any cause. Patients who are event-free will be censored at the date last seen

Anticancer Fund, Belgium

JP Moulton Charitable Foundation

Barts & The London NHS Trust

University College, London

Carcinosarcoma

Mixed Tumor, Mullerian

Malignant Mixed Mullerian Tumor

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with single agent AZD6738.

In second stage of trial, opening of this cohort depends on response rate in cohort 1A during first stage of trial.

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with AZD6738 in combination with olaparib.

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with NO loss of ARID1A expression treated with AZD6738 in combination with olaparib.

Women with other rare relapsed gynaecological cancers (endometrioid ovarian carcinoma, endometrioid endometrial carcinoma, cervical adenocarcinoma, cervical squamous, ovarian carcinosarcoma and endometrial carcinosarcoma) irrespective of ARID1A status, treated with AZD6738 in combination with olaparib.

AZD6738

Christy Toms

Katie Wilkinson

Michelle Everard

Susana Banerjee

ATARI trial tests the ATR inhibitor drug AZD6738 and a PARP inhibitor drug olaparib in patients with relapsed gynecological cancers to assess the response in groups of patients selected based on their cancer cell subtype and the presence of an abnormality in ARID1A gene.

ATARI is a multi-centre, open-label, multiple two-stage parallel cohorts phase II clinical trial for patients with relapsed gynaecological cancers, with ARID1A-deficient ('loss') and "no loss."

The trial tests the ATR inhibitor drug AZD6738 and a PARP inhibitor drug olaparib to assess the response in groups of patients selected based on their cancer cell subtype and the presence of an abnormality in ARID1A.

The treatment groups are: 1A - Women with clear cell subtype with (ovarian/uterus) ARID1A loss treated with AZD6738. 1B - Women with clear cell subtype with (ovarian/uterus) ARID1A loss treated with AZD6738 + olaparib. 2 - Women with clear cell subtype (ovarian/uterus) with no ARID1A loss treated with AZD6738 and olaparib. 3 - Women with other rare gynaecological cancers (carcinosarcoma, cervical, endometrioid type) irrespective of ARID1A loss treated with AZD6738 and olaparib.

Open-label, multiple two-stage parallel cohorts

ATr Inhibitor in Combination With Olaparib in Gynaecological Cancers With ARId1A Loss or no Loss

ATARI: ATr Inhibitor in Combination With Olaparib in Gynaecological Cancers With ARId1A Loss

A patient will be said to have had an overall objective response if they have a complete/partial response as assessed radiologically according to RECIST 1.1 at any point during trial treatment. A second scan to confirm response will be taken ≥ 4 weeks after the first scan showing an objective response.

The proportion of patients experiencing complete or partial response, or stable disease lasting at least 16 weeks from start of treatment as assessed radiologically by RECIST version 1.1.

Length of maintained response, measured according to RECIST v1.1

Measured according to RECIST v1.1 or death. Time to last tumour assessment will be used if patient has not progressed or died, and PFS time for the patient will be considered censored. PFS will be used to calculate the proportion of patients alive and free of progression at 6 months.

Measured according to RECIST v 1.1 or clinical progression of disease. Time to last tumour assessment will be used if patient has not progressed, and the patient will be considered censored. If the patient has died without prior progression, the patient will be censored at the date of death. Death will not count as a TTP event.

Adverse events thought to be related to drug will be graded according to NCI-CTCAE version 5.0, and coded using MedDRA (current version). Any dose reductions and delays in administration of drug due to toxicity will also be collected.

Defined by the time from start of treatment until death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I Trial of Defactinib and VS-6766.	NCT03875820	NSCLC Low Grade Serou... Endometrioid Ca... Pancreatic Canc...	VS-6766 Defactinib	18 Years -	Institute of Cancer Research, United Kingdom
Endometriosis and Frequency of Endometriosis-associated Ovarian Carcinomas (EAOC)	NCT01732432	Endometrioid Ca... Clear Cell Carc... Endometriosis		30 Years - 85 Years	University Hospital, Basel, Switzerland
Adaptive ChemoTherapy for Ovarian Cancer in Patients With Replased Platinum-sensitive High Grade Serous or High Grade Endometrioid Ovarian Cancer	NCT05080556	Ovarian Cancer Relapsed Ovaria... Fallopian Tube ... Peritoneal Canc... Endometrioid Ca... High Grade Sero... Ovary Cancer	Carboplatin	18 Years -	University College, London
ATr Inhibitor in Combination With Olaparib in Gynaecological Cancers With ARId1A Loss or no Loss	NCT04065269	Gynaecological ...	AZD6738 Olaparib	18 Years -	Institute of Cancer Research, United Kingdom

Spots Global Cancer Trial Database for endometrioid carcinoma