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

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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

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

Condition or disease Intervention/treatment Phase
Advanced Cancer Metastatic Cancer Ovarian Cancer Primary Peritoneal Cancer Fallopian Tube Cancer Drug: ART0380 Drug: Gemcitabine Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 13, 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


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 68 participants will participate in this dose escalation arm.
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.

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.
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

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.
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.

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.
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




Primary Outcome Measures :
  1. 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) ]
  2. 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. ]
  3. 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. ]

Secondary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. 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. ]
  4. Pharmacokinetic Analysis: Renal clearance of ART0380 [ Time Frame: Urine PK will be measured during Cycle 1. Cycle 1 is 21 days. ]
  5. 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. ]
  6. 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. ]
  7. 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. ]
  8. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04657068


Contacts
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Contact: Sarah Cannon Development Innovations 844-710-6157 CANN.InnovationsMedical@sarahcannon.com

Locations
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United States, Colorado
Sarah Cannon Research Institute at HealthONE Recruiting
Denver, Colorado, United States, 80218
Principal Investigator: Gerald Falchook, MD         
United States, Florida
Florida Cancer Specialists Recruiting
Orlando, Florida, United States, 32827
Principal Investigator: Cesar Perez, MD         
Florida Cancer Specialists Recruiting
Sarasota, Florida, United States, 34232
Principal Investigator: Manish Patel, MD         
United States, Oklahoma
Stephenson Cancer Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Principal Investigator: Kathleen Moore, MD         
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Principal Investigator: Melissa Johnson, MD         
Sponsors and Collaborators
Artios Pharma Ltd
Investigators
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Study Chair: Melissa Johnson, MD Tennessee Oncology
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Responsible Party: Artios Pharma Ltd
ClinicalTrials.gov Identifier: NCT04657068    
Other Study ID Numbers: ART0380C001
First Posted: December 8, 2020    Key Record Dates
Last Update Posted: September 29, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Artios Pharma Ltd:
Loss of Ataxia Telangiectasia Mutated (ATM) protein
Additional relevant MeSH terms:
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Fallopian Tube Neoplasms
Neoplasms by Site
Neoplasms
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Fallopian Tube Diseases
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs