Clinical trial NCT04657068: A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors
Official title: A Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the ATR Kinase Inhibitor ART0380 Administered Orally as Monotherapy and in Combination to Patients With Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Cancer
Metastatic Cancer
Ovarian Cancer
Primary Peritoneal Cancer
Fallopian Tube Cancer
Endometrial Cancer
Metastatic Colorectal Cancer
Pancreatic Ductal Adenocarcinoma
Acinar Cell Carcinoma
Keywords: Loss of Ataxia Telangiectasia Mutated (ATM) protein
Lead sponsor: Artios Pharma Ltd
Sponsor class: INDUSTRY
First posted: 2020-12-08
Enrollment: 597
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This clinical trial is evaluating a drug called ART0380 in participants with advanced or metastatic solid tumors. The main goals of this study are to:

* Find the recommended dose of ART0380 that can be given safely to participants alone and in combination with gemcitabine or irinotecan
* Learn more about the side effects of ART0380 alone and in combination with gemcitabine or irinotecan
* Learn more about the effectiveness of ART0380 alone and in combination with gemcitabine or irinotecan

Detailed description: ART0380 is a new investigational medicinal product that is a potent and selective inhibitor of Ataxia telangiectasia and Rad3-related (ATR). ART0380 is being developed as an oral anti-cancer agent for the treatment of participants with cancers that harbor defects in deoxyribonucleic acid (DNA) repair and in combination with agents including those that cause DNA damage.

This study is an open-label Phase I/IIa study designed to evaluate the safety, tolerability, PK and preliminary efficacy of ART0380 as monotherapy or in combination with gemcitabine or irinotecan in participants with advanced or metastatic solid tumors, advanced or solid tumors that fail to express Ataxia-Telangiectasia Mutated protein kinase (ATM) by immunohistochemistry, and high grade serous ovarian, primary peritoneal or fallopian tube carcinoma.

Eligibility criteria: General Inclusion Criteria:

* Signed informed consent
* Have not received a previous treatment targeting the ATR/CHK1 pathway
* Discontinued all previous treatments for cancer for at least 21 days or 5 half-lives, whichever is shorter, and recovered from the acute effects of therapy to CTCAE Grade ≤1. Palliative radiotherapy must have completed 1 week prior to start of study treatment.
* If patients have a known germline BRCA mutation or a cancer with a somatic BRCA mutations or which is HRD positive and for which there is an approved PARP inhibitor, participants should have received such treatment before participating in the study unless contra-indicated
* At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation by RECIST v1.1 or Prostate Cancer Working Group-3 Guidelines (PCWG-3)
* Acceptable hematologic, renal, hepatic, and coagulation functions independent of transfusions and granulocyte colony-stimulating factor
* Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis.
* Female patients of childbearing potential and male patients with female partners of childbearing potential are required to use highly effective contraception plus one barrier method during their participation in the study and for 7 months and 5 months respectively following the last dose. For male and female patients given gemcitabine or irinotecan, highly effective contraception plus one barrier method must be used from study entry until 6 months after the last dose of study treatment. Male patients are required to refrain from donating sperm and female patients are required to refrain from donating eggs, during their participation in the study and for 6 months following last dose.
* Estimated life expectancy of ≥12 weeks
* Reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures

Additional inclusion criteria for participants in dose escalation (Part A1):

* Advanced or metastatic cancer which is refractory to standard therapies, or for which no standard therapies exist, or for which the investigator feels no other active therapy is required for the duration of the study
* Performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) scale

Additional inclusion criteria for participants in dose escalation (Part A2):

* Advanced or metastatic cancer for which gemcitabine is an appropriate treatment. Prior treatment with gemcitabine is permitted.
* Performance status of 0-1 on the ECOG scale

Additional inclusion criteria for participants in dose escalation (Part A3):

* Advanced or metastatic cancer for which irinotecan is an appropriate treatment. Prior treatment with irinotecan is permitted.
* Performance status of 0-1 on the ECOG scale
* For food effect cohort only: Patients must be able to eat a high-fat meal within a 30 minute period, as provided by the study site.

Additional inclusion criteria for participants in dose expansion (Part B1):

* Patients with advanced or metastatic solid tumors with alterations to the ATM gene likely to predict for loss of ATM protein
* Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1
* Performance status of 0-1 on the ECOG scale
* For France only ART0380 Monotherapy; Patient that is not eligible for curative treatment, for whom all standard of care therapies have failed and no therapies known to provide clinical benefit are available.
* Combination arms; Patients for which irinotecan is an appropriate treatment. Prior treatment with irinotecan is permitted.
* For Spain only ART0380 Combination therapy, Patient that is not eligible for curative treatment, for whom standard of care therapies have failed.

Additional inclusion criteria for participants in dose expansion (Part B2):

* Patients with a known germline BRCA mutation, or a cancer with a known somatic BRCA mutation, or which is known to be HRD positive, and for which there is an approved PARP inhibitor should have received such treatment before participating in the study, unless contra-indicated.
* Females with histologically-confirmed diagnosis of high grade serous carcinoma of the ovary, fallopian tube or primary peritoneum that is not amenable to curative therapy
* Platinum-resistant disease, defined as disease progression within 6 months of last receipt of platinum-based chemotherapy. Patients must not have had primary platinum-refractory disease (disease that progressed during first-line platinum-based therapy).
* No more than one prior regimen in the platinum-resistant setting. Hormonal therapies and antiangiogenic therapies (as single agents) and PARP inhibitors used as maintenance therapy are not considered as separate lines of therapy. Patients should have previously received bevacizumab and chemotherapy unless contra-indicated.
* Have not received prior treatment with gemcitabine unless administered in combination with a platinum with no disease progression within 12 months after completion of that regimen
* Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1
* Performance status of 0-1 on the on the ECOG scale

Inclusion criteria specific to Part B3

* Persistent or recurrent endometrial cancer with biological selection.:
* Patients should have received taxane/platinum chemotherapy, unless contraindicated.
* Measurable disease.
* Performance status of 0-1 on the ECOG scale.

Inclusion criteria specific to Part B4

* Advanced or metastatic solid cancers of any histology with biological selection
* If a PD-1/PDL-1 inhibitor (eg, pembrolizumab) is approved and available for the patient's cancer, the patient should have received such treatment before participating in this study.
* Radiologically evaluable disease
* Performance status of 0-1 on the ECOG scale

Inclusion criteria specific to Part B5

* Metastatic CRC with alterations to the ATM gene
* Participants should have previously received appropriate prior lines of therapy in this setting.
* Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1.
* Performance status of 0-1 on the ECOG scale.

Inclusion criteria specific to Part B6:

* Metastatic or locally advanced PDAC or acinar cell carcinoma with alterations to the ATM gene
* Participants should have previously received prior lines of therapy in this setting
* Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1
* Performance status of 0-1 on the ECOG scale
* Serum albumin ≥3g/dL within 7 days prior to first dose.

General Exclusion Criteria:

* Women who are pregnant, breast feeding, or who plan to become pregnant while in the study or within 7 months after the last administration of study treatment
* Men who plan to father a child while in the study or within5 months after the last administration of study treatment
* Serious concomitant systemic disorder that would compromise the participants ability to adhere to the protocol including: one or more opportunistic HIV/AIDs-related infections within the past 12 months, a known hepatitis B virus, or known hepatitis C virus; documented active or chronic tuberculosis infection; malignancy prior to the one currently being treated that is not in remission
* Have ongoing interstitial lung disease or pneumonitis (whether symptomatic or asymptomatic).
* Moderate or severe cardiovascular disease
* Valvulopathy that is severe, moderate, or deemed clinically significant
* Documented major electrocardiogram (ECG) abnormalities which are clinically significant
* Symptomatic or uncontrolled brain metastases, spinal cord compression, or leptomeningeal disease requiring concurrent treatment
* Received a live vaccine within 30 days before the first dose of study treatment
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate
* Recent major surgery within 4 weeks prior to entry into the study or minor surgery within 1 week of entry into the study
* Significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment
* Currently enrolled in a clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study

Additional exclusion criteria for participants in dose escalation (Part A3, B1, B5, and B6 in combination with irinotecan):

* Patients who have symptoms or signs of clinically unacceptable deterioration of the primary disease at the time of screening.
* Patients receiving inhibitors of UGT1A1 within 2 weeks before the first dose of study treatment
* Part B5 only: Patients who have received fruquintinib or regorafenib or trifluridine/tipiracil.
* Part A3 Fed-fasted cohort only: Patients receiving acid reducing agents within 1 week before the first dose of study treatment will be excluded
* Part B6 only: Neuroendocrine (carcinoid, islet cell) or adenosquamous carcinoma pancreatic cancer

Primary outcomes:
measure: Part A: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities (DLTs) from ART0380 monotherapy and in combination with gemcitabine or irinotecan
timeFrame: From Cycle 0 Day -2 to Cycle 1 Day 21. Each cycle is 21 days.
measure: Parts B1/B3/B4/B5/B6: Number of participants with adverse events following administration of ART0380 monotherapy and/or in combination with irinotecan
timeFrame: From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380. Each cycle is 21 days.
measure: Part B2: Progression free survival by RECIST 1.1 in participants receiving ART0380 in combination with gemcitabine or gemcitabine alone
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.
Secondary outcomes:
measure: Part B2: Number of participants with adverse events following administration of ART0380 in combination with gemcitabine or gemcitabine alone
timeFrame: From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380 or gemcitabine. Each cycle is 21 days.
measure: Pharmacokinetic Analysis (single dose): determine the plasma concentration of ART0380 when given alone and in combination
timeFrame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days.
measure: Pharmacokinetic Analysis (multiple dose): determine the plasma concentration of ART0380 when given alone and in combination
timeFrame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days.
measure: Pharmacokinetic Analysis: Renal clearance of ART0380
timeFrame: Urine PK will be measured during Cycle 1. Cycle 1 is 21 days.
measure: Parts A1, A2, A3, B1, B2, B3, B4, B5, and B6: Objective response rate based on RECIST 1.1
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.
measure: Parts A1, A2, A3, B1, B2, B3, B4, B5, and B6: Duration of response based on RECIST 1.1
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.
measure: Parts A1, A2, A3, B1, B2, B3, B4, B5, and B6: Progression free survival based on RECIST 1.1
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.
measure: Assess tumor biopsies by immunohistochemistry (IHC) for loss of Ataxia Telangiectasia Mutated (ATM) protein
timeFrame: Prior to dosing on Cycle 1 Day 1
measure: Pharmacokinetic Analysis (single and multiple dose where the data allow)
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Time to Maximum plasma concentration of Irinotecan and ART0380
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Estimated Renal Clearance of Irinotecan and ART0380
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the concentration-time curve over the dosing interval (AUC(0-infinity)
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area Under The Curve Plasma Concentration Time Curve from zero to 12 hours (AUC0-12)
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area Under the Plasma Concentration Time Curve from zero to 24 hours (AUC0-24)
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the curve concentration-time curve over the dosing interval (AUC(0-infinity))
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: The Volume of Distribution based on the terminal Phase (Vz)
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the Plasma concentration time curve from zero to the end of the dosing interval (AUCtau)
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Maximum plasma Concentration (Cmax) in a fasting and fed state.
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Time to Maximum plasma concentration (Tmax) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area Under The Curve Plasma Concentration Time Curve from zero to the time of last plasma concentration (AUC0-t) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Terminal half-life (t1/2) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the concentration-time curve over the dosing interval (AUC(0-tau)) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area Under The Curve Plasma Concentration Time Curve over the last 12-h dosing interval (AUC012) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the concentration-time curve over the dosing interval (AUC(0-infinity)) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the concentration-time curve for Oral Clearance (CL/F) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
measure: Pharmacokinetic Analysis: Area under the concentration-time curve for Volume of Distribution (Vz/F) in a fasting and fed state
timeFrame: PK will be measured during Cycle 1. Cycle 1 is 21 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas - Winthrop P. Rockefeller Cancer Institute
state: Arkansas
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Santa Barbara
country: United States
facility: Sansum Clinic
state: California
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Denver
country: United States
facility: Sarah Cannon Research Institute at HealthONE
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Orlando
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Hinsdale
country: United States
facility: Hope and Healing Cancer Services
state: Illinois
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Baton Rouge
country: United States
facility: Our Lady of the Lake
state: Louisiana
city: Columbia
country: United States
facility: Maryland Oncology Hematology - Primary
state: Maryland
city: Maple Grove
country: United States
facility: Minnesota Oncology Hematology
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: East Syracuse
country: United States
facility: Hematology Oncology Associates of Central New York
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care Primary
state: Ohio
city: Maumee
country: United States
facility: Taylor Cancer Research Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University
state: Oklahoma
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization
state: Pennsylvania
city: Chattanooga
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Memphis
country: United States
facility: Baptist Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology - Central/South Texas
state: Texas
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Flower Mound
country: United States
facility: Texas Oncology - Northeast Texas
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology - San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Cedex
city: Bordeau
country: France
facility: Institut Bergonie
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Sabadell
country: Spain
facility: H. Parc Tauli
state: Barcelona
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
state: Catalonia
city: Barcelona
country: Spain
facility: Next Oncology Barcelona, IOB
state: Cataluna
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
state: Comunidad De Madrid
city: Pozuelo De Alarcón
country: Spain
facility: Next - Hospital Quironsalud Madrid
state: Comunidad De Madrid
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
state: Murcia
city: Madrid
country: Spain
facility: Clínica Universidad de Navarra
state: Planta -2
city: A Coruña
country: Spain
facility: Hospital Teresa Herrera (CHUAC)
city: Badalona
country: Spain
facility: Institut Català d'Oncologia Badalona - Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology (VIHO)
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: ICO Hospitalet
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia de Córdoba
city: Girona
country: Spain
facility: Hospital Universitari Doctor Josep Trueta- ICO de Girona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: MD Anderson Cancer Center (Madrid
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: START Madrid Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: START Madrid (Hospital San Chinarro)
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Incliva Biomedical Research Institute, University of Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
Study officials:
affiliation: Tennessee Oncology
name: Melissa Johnson, MD
role: STUDY_CHAIR
affiliation: Clinica Universidad de Navarra, Madrid
name: Antonio Gonzalez, MD, PHD
role: STUDY_CHAIR
affiliation: Oklahoma University
name: Susanna Ulahannan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania / Abramson Cancer Center
name: Kim Reiss Binder, MD
role: PRINCIPAL_INVESTIGATOR
References: