A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors

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

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

Study Overview

• Status: Recruiting
• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Metastatic Cancer; Advanced Cancer; Primary Peritoneal Cancer
• Intervention / Treatment: Drug: ART0380; Drug: Irinotecan; Drug: Gemcitabine

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.

• Study Type: Interventional
• Enrollment (Estimated): 462
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Sarah Cannon Development Innovations; Phone Number: 844-710-6157; Email: SCRI.InnovationsMedical@scri.com

Study Locations

• France
  • Cedex
    • Villejuif, Cedex, France, 94805
      • Recruiting
      • Institut Gustave Roussy
      • Contact: Capucine Baldini, MD
• Spain
  • A Coruña, Spain, 15006
    • Recruiting
    • Hospital Teresa Herrera (CHUAC)
  • Badalona, Spain, 08916
    • Recruiting
    • Institut Català d'Oncologia Badalona - Hospital Germans Trias i Pujol
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08903
    • Recruiting
    • ICO Hospitalet
  • Córdoba, Spain, 14004
    • Recruiting
    • Hospital Universitario Reina Sofia de Cordoba
  • Girona, Spain, 17007
    • Recruiting
    • Hospital Universitari Doctor Josep Trueta- ICO de Girona
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28007
    • Recruiting
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28033
    • Recruiting
    • MD Anderson Cancer Center (Madrid
  • Malaga, Spain, 29010
    • Recruiting
    • Hospital Universitario Virgen de la Victoria
  • Málaga, Spain, 29010
    • Recruiting
    • Hospital Universitario Virgen de la Victoria
  • Sevilla, Spain, 41013
    • Recruiting
    • Hospital Virgen del Rocio
  • Valencia, Spain, 46010
    • Recruiting
    • Incliva Biomedical Research Institute, University of Valencia
  • Zaragoza, Spain, 50009
    • Recruiting
    • Hospital Universitario Miguel Servet
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Recruiting
      • H. Parc Tauli
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Recruiting
      • Hospital Clinico Universitario Virgen de la Arrixaca
  • Planta -2
    • Madrid, Planta -2, Spain, 28027
      • Recruiting
      • Clinica Universidad de Navarra
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Recruiting
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, W1G 6AD
    • Recruiting
    • Sarah Cannon Research Institute UK
    • Principal Investigator: Elisa Fontana
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guy's and St Thomas' NHS Foundation Trust
    • Contact: Rebecca S. Kristeleit, MD
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • Recruiting
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Recruiting
      • University of Arkansas - Winthrop P. Rockefeller Cancer Institute
  • Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Sarah Cannon Research Institute at HealthONE
      • Principal Investigator: Gerald Falchook, MD
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Recruiting
      • Florida Cancer Specialists
      • Principal Investigator: Fadi Kayali, MD
    • Orlando, Florida, United States, 32827
      • Completed
      • Florida Cancer Specialists
    • Sarasota, Florida, United States, 34232
      • Recruiting
      • Florida Cancer Specialists
      • Principal Investigator: Manish Patel, MD
    • West Palm Beach, Florida, United States, 33401
      • Recruiting
      • Florida Cancer Specialists
      • Principal Investigator: Barry Scott Berman, MD
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • Stephenson Cancer Center
      • Principal Investigator: Kathleen Moore, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization
      • Principal Investigator: Babar Bashir, MD
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Recruiting
      • Tennessee Oncology, PLLC
      • Principal Investigator: Edward Riker Arrowsmith, MD
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Tennessee Oncology
      • Principal Investigator: Melissa Johnson, MD
  • Texas
    • Dallas, Texas, United States, 75230
      • Recruiting
      • Mary Crowley Cancer Research
      • Principal Investigator: Minal Barve, MD
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

General Inclusion Criteria:

• Signed written 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 0-2 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 0-2 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

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

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; known history of clinical diagnosis of tuberculosis; 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 and B1 in combination with irinotecan):

• Patients who are known to be homozygous for the UGT1A1 *6 or *28. (UGT1A1 7/7 genotype), or simultaneously heterozygous for the UGT1A1 *6 and *28. (UGT1A1 7/7 genotype)
• Patients receiving inhibitors of UGT1A1 within 2 weeks before the first dose of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A1; Part A1 will evaluate intermittent and continuous dosing of ART0380 monotherapy. Treatment will be given in 21-day cycles. Up to 50 participants will participate in this dose-escalation arm.	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.
Experimental: Part A2; Part A2 will evaluate intermittent dosing of ART0380 in combination with gemcitabine in 21-day cycles. Up to 21 participants will participate in this dose escalation arm.	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.; Drug: Gemcitabine; Gemcitabine will be administered on Days 1 and 8 of a 21-day cycle.; Other Names: Gemzar
Experimental: Part A3; Part A3 will evaluate intermittent dosing of ART0380 in combination with irinotecan in 21-day cycles. Up to approximately 12 participants will participate in this dose escalation arm.	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.; Drug: Irinotecan; Irinotecan will be administered as a 90-minute infusion on Days 1 and 8 of a 21 day cycle.; Other Names: Camptosar; Camptothecin-11
Experimental: Part B2; In Part B2, up to 110 participants with high grade serous ovarian, primary peritoneal, or fallopian tube carcinoma will be randomized (open label) 1:1 to either ART0380 in combination with gemcitabine or gemcitabine alone.	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.; Drug: Gemcitabine; Gemcitabine will be administered on Days 1 and 8 of a 21-day cycle.; Other Names: Gemzar
Experimental: Part B3; Part B3: Patients with persistent or recurrent endometrial cancer (EC) will receive ART0380 monotherapy on either a continuous daily dose or on an intermittent schedule for a 21-day cycle..	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.
Experimental: Part B4; Patients with advanced or metastatic solid tumors will receive ART0380 monotherapy on either a continuous daily dose or on an intermittent schedule for a 21-day cycle.	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.
Experimental: Part B1; In Part B1, up to 6 cohorts making up to a total of approximately 180 participants with solid cancers with alterations in the ATM (ataxia-telangiectasia mutated) gene likely to predict for loss of ATM protein will be treated with either; ART0380 monotherapy Or; ART0380 in combination with irinotecan	Drug: ART0380; Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.; Drug: Irinotecan; Irinotecan will be administered as a 90-minute infusion on Days 1 and 8 of a 21 day cycle.; Other Names: Camptosar; Camptothecin-11

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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		From Cycle 0 Day -2 to Cycle 1 Day 21. Each cycle is 21 days.
Part B2: Progression free survival by RECIST 1.1 in participants receiving ART0380 in combination with gemcitabine or gemcitabine alone	Progression free survival (PFS)	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.
Parts B1/B3/B4: Number of participants with adverse events following administration of ART0380 monotherapy and/or in combination with irinotecan	Safety reported as incidence of adverse events	From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380. Each cycle is 21 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B2: Number of participants with adverse events following administration of ART0380 in combination with gemcitabine or gemcitabine alone		From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380 or gemcitabine. Each cycle is 21 days.
Pharmacokinetic Analysis (single dose): determine the plasma concentration of ART0380 when given alone and in combination		PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days.
Pharmacokinetic Analysis (multiple dose): determine the plasma concentration of ART0380 when given alone and in combination		PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days.
Pharmacokinetic Analysis: Renal clearance of ART0380		Urine PK will be measured during Cycle 1. Cycle 1 is 21 days.
Assess tumor biopsies by immunohistochemistry (IHC) for loss of Ataxia Telangiectasia Mutated (ATM) protein	Where available archival tumor samples will be obtained for analysis of loss of ATM protein by IHC. If an archival tumor sample is not available, a pre-dose tumor biopsy must be taken.	Prior to dosing on Cycle 1 Day 1
Parts A1, A2, A3, B1, B2, B3 and B4: Objective response rate based on RECIST 1.1		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.
Parts A1, A2, A3, B1, B2, B3 and B4: Duration of response based on RECIST 1.1		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.
Parts A1, A2, A3, B1, B3 and B4: Progression free survival based on RECIST 1.1		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.

Collaborators and Investigators

• Sponsor: Artios Pharma Ltd
• Investigators: Study Chair: Melissa Johnson, MD, Tennessee Oncology; Study Chair: Antonio Gonzalez, MD, PHD, Clinica Universidad de Navarra, Madrid

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2020
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (Actual): December 8, 2020

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Loss of Ataxia Telangiectasia Mutated (ATM) protein
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Adnexal Diseases; Fallopian Tube Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Fallopian Tube Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan; Camptothecin; Gemcitabine
• Other Study ID Numbers: ART0380C001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No