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
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
NCT #
NCT04657068
Condition(s)
Solid Tumors
Molecular Target(s)
ATR
Drug Classification(s)
Small Molecule
Agents(s)
TNFR2
Phase(s)
I/Iia
Mechanism of Action
ART0380 selectively targets and inhibits ATR activity and blocks the downstream phosphorylation of the serine/threonine protein kinase checkpoint kinase 1 (CHK1). This prevents ATR-mediated signaling, which results in the inhibition of DNA damage checkpoint activation, the disruption of DNA damage repair, and the induction of tumor cell apoptosis.
Purpose
- What is the highest dose of the Study Drug that can be given to cancer patients without causing significant side effects?
- How often can the Study Drug be given to cancer patients?
- What are the side effects of the Study Drug when given alone and in combination with irinotecan?
- What effect does the Study Drug have on your tumor when given in combination with irinotecan?
- How is the Study Drug distributed, broken down, and passed out of your body?
- How does the Study Drug affect biomarkers? Biomarkers are substances in your body that can be used to detect a disease or to find out how the cancer is responding to study treatment.
- These substances in blood and optional tumor tissue will be tested to learn if the Study Drug changes the way the cancer behaves.
- If some of your tumor tissue has been stored (archival tumor tissue), it will be analyzed to see if it contains a protein called ‘ATM’ (ataxia-telangiectasia mutated protein kinase). If archival tumor tissue is not available, a fresh tumor sample will be taken before your first dose of Study Drug.
- Optional tumor samples and an optional blood sample will be taken during the study if you 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 or gemcitabine is an appropriate treatment. Prior treatment with irinotecan or gemcitabine is permitted.
- 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
- 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, 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
- 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
No prior therapy targeting the ATR/CHK1 pathway
Location
MCD
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