A clinical study to assess the safety and efficacy of oral ART0380 as a single agent or in combination in solid tumors
- Conditions
- Advanced or Metastatic Solid Tumours
- Registration Number
- 2024-511534-12-00
- Lead Sponsor
- Artios Pharma Limited
- Brief Summary
Part A: Safety and tolerability of ART0380 oral in patients with advanced or metastatic solid tumors and to determine the maximum (MTDs and/or recommended Phase II doses/schedules (RP2Ds) of ART0380 as monotherapy or in combination with gemcitabine or in combination with irinotecan.
Parts B1/B3/B4/B5/B6: To further assess the safety and tolerability of ART0380 given orally as monotherapy, and/or ART0380 in combination with irinotecan RP2Ds.
Part B2: To compare the efficacy of ART0380 in combination with gemcitabine versus gemcitabine alone in patients with high grade serous ovarian, primary peritoneal or fallopian tube carcinoma that is resistant to platinum (PFI <6 months).
- 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.
Recruitment & Eligibility
- Status
- Ongoing, recruiting
- Sex
- Not specified
- Target Recruitment
- 210
Signed informed consent
Specific criteria for B5:• Metastatic colorectal cancer (CRC) •Patients must have previously received fluoropyrimidine, oxaliplatin and irinotecanbased chemotherapy. Patients whose tumors are eligible for targeted therapies must have received such therapies if appropriate, indicated for the patient and available •Patients must have received a maximum of 2 prior chemotherapy regimens for the treatment of CRC.•Have at least 1 measurable lesion assessable by RECIST v1.1.•ECOG 0-1
Not previous treatment targeting the ATR/CHK1 pathway
Discontinued all previous treatments for cancer for at least 21d or 5 half-lives, whichever is shorter, and recovered from the acute effects of therapy to CTCAE Grade ≤1. Palliative Rt completed 1 week prior to start of study treatment
If known germline BRCA mutation or a cancer with a somatic BRCA mutation 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 lesión (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
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 last dose
Estimated life expectancy of ≥12 weeks
Specific criteria for Part B6 •Patients with metastatic or locally advanced PDAC or acinar cell carcinoma. •Patients must have received a maximum of 1 prior multiagent chemotherapy regimen in the advanced setting for the treatment of PDAC or acinar cell carcinoma. Prior treatment with irinotecan is permitted. •Have at least 1 measurable lesion assessable by RECIST v1.1. •Performance status of 0-1 on the ECOG scale. • Serum albumin ≥3g/dL within 7 days prior to first dose.
Reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
Specific criteria for A1:•Advanced or metastatic Ca refractory to standard therapies, or for which no standard therapies exist, or for which the investigator feels no other active therapy is required for study duration• ECOG 0-2.
Specific criteria for A2:•Advanced or metastatic Ca for which gemcitabine is an appropriate treatment. Prior treatment with gem. Is permitted. •ECOG 0-1
Specific criteria for A3:• Advanced or metastatic Ca for which irinotecan is an appropriate treatment. Prior irino. is permitted •ECOG 0-1 •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.
Specific criteria for B1:•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 by RECIST v1.1• ECOG 0-1•Combination arms: pat. for which irinotecan is an appropriate treatment. Prior treatment with irino is permitted
Specific criteria for B2: •Known germline BRCA mutation, or a Ca 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 contraindicated•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. •Plt-resistant disease, defined as disease progression within 6 months of last receipt of Plt-based chemotherapy. No primary Plt-refractory disease (disease that progressed during firstline Plt-based therapy). •No more than one prior regimen in the Plt-resistant setting. Hormonal therapies and antiangiogenic therapies (as single agents) and PARP inhibitors used as maintenance are not considered as separate lines of therapy. Prior bevacizumab and chemotherapy unless contra-indicated•Have not received prior treatment with gemcitabine unless administered in combination with a Plt with no disease progression within 12 months after completion of that regimen • Have at least 1 measurable lesión assessable by RECIST v1.1• ECOG 0-1
Specific criteria for B3: • Persistent or recurrent endometrial Ca with biological selection• Pat. should have received taxane/Plt, unless contraindicated• At least 1 measurable lesion assessable by RECIST v1.1•ECOG 0-1
Specific criteria for B4:• Advanced or metastatic solid cancers of any histology with biological selection• If a PD-1/PDL-1 inhibitor is approved and available, pat. should have received such treatment before participating• At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed by RECIST v1.1 or PCWG-3 • ECOG 0-1
Women who are pregnant, breast feeding, or who plan to become pregnant while in the study or within 7 month after the last administration of study treatment
Have a history of allergy or hypersensitivity to study drug components
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
Exclusion criteria for A3/B1/B5/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 will be excluded •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.
Men who plan to father a child while in the study or within 5 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, hepatitis B virus, or 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).
Have moderate or severe cardiovascular disease - Have valvulopathy that is severe, moderate, or deemed clinically significant. - Have 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Primary Outcome Measures
Name Time Method Part A: Incidence of dose-limiting toxicities (DLTs) Part A: Incidence of dose-limiting toxicities (DLTs)
Parts B1/B3/B4/B5: Incidence and severity of AEs (CTCAE v5.0) Parts B1/B3/B4/B5: Incidence and severity of AEs (CTCAE v5.0)
Part B2: Progression free survival (RECIST v1.1) Part B2: Progression free survival (RECIST v1.1)
- Secondary Outcome Measures
Name Time Method Part B2 Incidence and severity of AEs Part B2 Incidence and severity of AEs
ART0380 Plasma concentration data. ART0380 Plasma concentration data.
ART0380 renal clearance data ART0380 renal clearance data
Part A and part B1/B3/B4/B5: Objective Response Rate, Duration of Response (based on RECIST v1.1). Progression free survival Part A and part B1/B3/B4/B5: Objective Response Rate, Duration of Response (based on RECIST v1.1). Progression free survival
Part B2: Objective Response Rate, Duration of Response (based on RECIST v1.1). Part B2: Objective Response Rate, Duration of Response (based on RECIST v1.1).
Archival tumor or pre-dose tumor biopsy: Correlation of lesions in (or indicative of lesions in) DNA repair pathways Archival tumor or pre-dose tumor biopsy: Correlation of lesions in (or indicative of lesions in) DNA repair pathways
Irinotecan and its metabolite SN-38 plasma concentration data Irinotecan and its metabolite SN-38 plasma concentration data
Plasma concentration data • Single dose PK parameters of ART0380 administered in fasting and fed states Plasma concentration data • Single dose PK parameters of ART0380 administered in fasting and fed states
Trial Locations
- Locations (28)
Hospital General Universitario De Elche
🇪🇸Elche, Spain
Hospital Universitario Reina Sofia
🇪🇸Cordoba, Spain
Hospital Universitario Quironsalud Madrid
🇪🇸Pozuelo De Alarcon, Spain
Hospital Universitari Arnau De Vilanova De La Gerencia Territorial De Lleida
🇪🇸Lleida, Spain
Hospital Universitario Virgen De La Victoria
🇪🇸Malaga, Spain
Parc Tauli Hospital Universitari
🇪🇸Sabadell, Spain
Hospital Universitario Hm Sanchinarro
🇪🇸Madrid, Spain
Institut Catala D'oncologia
🇪🇸Badalona, Spain
Hospital Universitario 12 De Octubre
🇪🇸Madrid, Spain
Hospital Universitari Vall D Hebron
🇪🇸Barcelona, Spain
Scroll for more (18 remaining)Hospital General Universitario De Elche🇪🇸Elche, SpainElena AsensioSite contact+34966616250helenasensio@yahoo.es