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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04657068
Recruitment Status : Recruiting
First Posted : December 8, 2020
Last Update Posted : September 29, 2021
Sponsor:
Information provided by (Responsible Party):
Artios Pharma Ltd

Tracking Information
First Submitted Date  ICMJE December 1, 2020
First Posted Date  ICMJE December 8, 2020
Last Update Posted Date September 29, 2021
Actual Study Start Date  ICMJE January 13, 2021
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2021)
  • Part A: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities (DLTs) from ART0380 monotherapy and in combination with gemcitabine [ Time Frame: 24 days (Cycle 0 Day -3 to Cycle 1 Day 21) ]
  • Part B1: Number of participants with adverse events following administration of ART0380 [ Time Frame: From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380. 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 [ Time Frame: 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. ]
Original Primary Outcome Measures  ICMJE
 (submitted: December 1, 2020)
  • Part A: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities (DLTs) from ART0380 monotherapy and in combination with gemcitabine [ Time Frame: 21 days (Cycle 1 Day 1 to Cycle 1 Day 21) ]
  • Part B1: Number of participants with adverse events following administration of ART0380 [ Time Frame: From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380. 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 [ Time Frame: 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. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2021)
  • Part B2: Number of participants with adverse events following administration of ART0380 in combination with gemcitabine or gemcitabine alone [ Time Frame: 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 with gemcitabine [ Time Frame: 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 with gemcitabine [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis: Renal clearance of ART0380 [ Time Frame: Urine PK will be measured during Cycle 1. Cycle 1 is 21 days. ]
  • Parts A1, A2, B1, and B2: Objective response rate based on RECIST 1.1 [ Time Frame: 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, B1, and B2: Duration of response based on RECIST 1.1 [ Time Frame: 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 and B1: Progression free survival based on RECIST 1.1 [ Time Frame: 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. ]
  • Assess tumor biopsies by immunohistochemistry (IHC) for loss of Ataxia Telangiectasia Mutated (ATM) protein [ Time Frame: Prior to dosing on Cycle 1 Day 1 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 1, 2020)
  • Part B2: Number of participants with adverse events following administration of ART0380 in combination with gemcitabine or gemcitabine alone [ Time Frame: 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): Maximum plasma concentration (Cmax) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Time to maximum plasma concentration (tmax) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Terminal elimination half-life (t1/2) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Area under the plasma concentration-time curve up to the last measurable concentration (AUC0-t) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Area under the plasma concentration-time curve from time zero to 12 hours (AUC0-12) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Apparent oral plasma clearance (CL/F) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (single dose): Apparent volume of distribution (Vz/F) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Maximum steady state plasma concentration (Cmax ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Time to maximum plasma concentration at steady state (tmax ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Minimum steady state plasma concentration (Cmin ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Terminal elimination half-life at steady state (t1/2 ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Area under the plasma concentration-time curve up to the last measurable concentration at steady state (AUC0-t ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Area under the plasma concentration-time curve from time zero to 12 hours at steady state (AUC0-12 ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Area under the plasma concentration-time curve from time zero to 24 hours at steady state (AUC0-24 ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Area under the plasma concentration-time curve at steady state (AUC ss) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Steady state apparent oral plasma clearance (CLss/F) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis (multiple dose): Accumulation ratio (Rac) for ART0380 [ Time Frame: PK will be measured at each cycle from Cycle 0 to Cycle 4. Each cycle is 21 days. ]
  • Pharmacokinetic Analysis: Renal clearance for ART0380 [ Time Frame: Urine PK will be measured during Cycle 1. Cycle 1 is 21 days. ]
  • Parts A1, B1, and B2: Best overall response based on RECIST 1.1 [ Time Frame: 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, B1, and B2: Objective response rate based on RECIST 1.1 [ Time Frame: 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, B1, and B2: Disease control rate based on RECIST 1.1 [ Time Frame: 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, B1, and B2: Duration of response based on RECIST 1.1 [ Time Frame: 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, B1, and B2: Change in tumor size based on RECIST 1.1 [ Time Frame: 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 and B1: Progression free survival based on RECIST 1.1 [ Time Frame: 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, B1, and B2: Overall survival [ Time Frame: Every 12 weeks from baseline up to approximately 24 months ]
  • Parts A1 and B1: Change in serological tumor markers [ Time Frame: 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. ]
  • Part B2: Change in CA-125 serological tumor marker in participants with ovarian cancer receiving ART0380 in combination with gemcitabine or gemcitabine alone [ Time Frame: 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. ]
  • Change in markers predictive of ART0380 activity [ Time Frame: Prior to dosing on Cycle 1 Day 1 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors
Official Title  ICMJE 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
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
  • Learn more about the side effects of ART0380 alone and in combination with gemcitabine
  • Learn more about the effectiveness of ART0380 alone and in combination with 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 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Cancer
  • Metastatic Cancer
  • Ovarian Cancer
  • Primary Peritoneal Cancer
  • Fallopian Tube Cancer
Intervention  ICMJE
  • Drug: ART0380
    Participants will receive ART0380 by mouth either intermittently (once daily 3 days on, 4 days off or days 2-4 and 9-11) or continuously (once daily each day) in 21 day cycles.
  • Drug: Gemcitabine
    Gemcitabine will be administered at a dose of 1000 mg/m^2 on Days 1 and 8 of a 21 day cycle.
    Other Name: Gemzar
Study Arms  ICMJE
  • Experimental: Part A1
    Part A1 will evaluate intermittent and continuous dosing of ART0380 monotherapy. Treatment will be given in 21 day cycles. Up to 68 participants will participate in this dose escalation arm.
    Intervention: Drug: ART0380
  • Experimental: Part A2
    Part A2 will evaluate intermittent dosing of ART0380 in combination with gemcitabine in 21-day cycles. Up to 12 participants will participate in this dose escalation arm.
    Interventions:
    • Drug: ART0380
    • Drug: Gemcitabine
  • Experimental: Part B1
    Part B1 will evaluate ART0380 monotherapy in up to 40 participants with solid cancers that fail to express ATM (ataxia-telangiectasia mutated) protein.
    Intervention: Drug: ART0380
  • Experimental: Part B2
    In Part B2, up to 60 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.
    Interventions:
    • Drug: ART0380
    • Drug: Gemcitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 1, 2020)
180
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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 via immunohistochemistry (IHC) for loss of ATM protein
  • Female patients of childbearing potential and male patients with female partners of childbearing potential are required to use highly effective contraception
  • 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 expansion (Part B1):

  • Patients with advanced or metastatic solid tumors with loss of ATM protein by IHC
  • Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1
  • Performance status of 0-2 on the ECOG scale

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

  • 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 or second-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

General Exclusion Criteria:

  • Women who are pregnant, breast feeding, or who plan to become pregnant while in the study or within 4 weeks after the last administration of study treatment
  • Men who plan to father a child while in the study or within 16 weeks 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, hepatitis B virus, or hepatitis C virus; known history of clinical diagnosis of tuberculosis; malignancy prior to the one currently being treated that is not in remission
  • Evidence of 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sarah Cannon Development Innovations 844-710-6157 CANN.InnovationsMedical@sarahcannon.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04657068
Other Study ID Numbers  ICMJE ART0380C001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Artios Pharma Ltd
Study Sponsor  ICMJE Artios Pharma Ltd
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Melissa Johnson, MD Tennessee Oncology
PRS Account Artios Pharma Ltd
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP