| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Solid Tumours |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic cancer is that which has spread from its original site to new area(s) of the body. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A: To assess the safety and tolerability of ART0380 given orally in patients with advanced or metastatic solid tumors and to determine the maximum tolerated doses (MTDs) and/or recommended Phase II doses/schedules (RP2Ds) of ART0380 as monotherapy or in combination with gemcitabine or in combination with irinotecan.
Part B1: To further assess the safety and tolerability of ART0380 given orally as monotherapy at RP2Ds.
Part B2: To compare the efficacy of ART0380 in combination with gemcitabine compared with gemcitabine alone in patients with high grade serous ovarian, primary peritoneal or fallopian tube carcinoma that is resistant to platinum (PFI <6 months).
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| E.2.2 | Secondary objectives of the trial |
1. Part B2: To further assess the safety and tolerability of ART0380 at the RP2D in combination with gemcitabine compared with gemcitabine alone.
2. To determine the pharmacokinetics of ART0380 following both single and multiple oral dosing of ART0380 in patients with advanced or metastatic solid tumors.
3. To assess preliminary signs of efficacy with ART0380 as monotherapy in advanced or metastatic solid tumors (Part A1), in combination with gemcitabine (Part A2), in combination with irinotecan (Part A3) or in advanced or metastatic solid tumors with alterations in the ATM gene likely to predict for loss of ATM protein (Part B1).
4. Part B2: To assess signs of efficacy for ART0380 in combination with gemcitabine vs gemcitabine alone in patients with high grade serous ovarian, primary peritoneal or fallopian tube carcinoma that is resistant to platinum (PFI <6 months).
5. To assess markers in pre-dose tumor samples that may be predictive of the activity of ART0380. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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 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 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 0-1 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
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
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| E.4 | Principal exclusion criteria |
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) Patients with a previous history of these conditions which have resolved may be permitted to enter the study after discussion with the medical monitor.
•Moderate or severe cardiovascular disease
o Valvulopathy that is severe, moderate, or deemed clinically significant
o 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
Addition exclusion criteria specific to Part A3
•Patients who are 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 will be excluded.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: Incidence of dose-limiting toxicities (DLTs); incidence and severity of adverse events (AEs) (CTCAE v5.0); physical examination; vital signs; electrocardiogram (ECG) parameters; hematology; clinical chemistry (including liver function tests); urinalysis and coagulation.
Part B1: Incidence and severity of AEs (CTCAE v5.0); physical examination; vital signs; ECG parameters; hematology; clinical chemistry (including liver function tests); urinalysis and coagulation.
Part B2: Progression free survival (RECIST v1.1). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety assessments: will be performed throughout the trial.
Efficacy assessments: every 6 weeks (±7 days) from 1st dose for 18 weeks, then every 9 weeks.
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| E.5.2 | Secondary end point(s) |
1. Part B2 Incidence and severity of AEs (CTCAE v5.0); physical examination; vital signs; ECG parameters; hematology; clinical chemistry (including liver function tests); urinalysis and coagulation.
2. Plasma concentration data.
• Single dose: Cmax, tmax, t1/2, AUC0-24, AUC0-t, AUC0-12, AUC0-inf, CL/F and Vz/F.
• Multiple dose: Cmax ss, tmax ss, Cmin ss, t1/2 at steady state, AUC0-t ss, AUC0-12 ss, AUC0-24 ss, AUCss and CLss/F and accumulation ratio (Rac).
Urine Concentration data, renal clearance (CLR).
3. Part A and part B1: Best Overall Response, Objective Response Rate, Disease Control Rate, Duration of Response, change in tumor size (based on RECIST v1.1 and PCWG-3).
Serological tumor markers (eg, CA-125, PSA, CEA) where applicable.
CA-125 response, CA-125 progression, PSA response, PSA progression where applicable.
Progression free survival and Overall survival.
4. Part B2: Best Overall Response, Objective Response Rate, Disease Control Rate, Duration of Response and change in tumor size (based on RECIST v1.1).
CA-125 response. CA-125 progression and Overall survival.
5. Archival tumor or pre-dose tumor biopsy: Correlation of lesions in (or indicative of lesions in) DNA repair pathways (such as, but not limited to, loss of ATM protein by IHC) with patient benefit from ART0380.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Safety assessments will be performed throughout the trial.
2. Pharmacokinetics: the PK parameters will be reported for Cycle 0 Day -2 (single dose) and Cycle 1 Day 15 and 16 (continuous) and Day 17 and 18 (Intermittent) (multiple-dosing).
3. Efficacy assessments: in Parts A/B1-Every 6 weeks (±7 days) from 1st dose for 18 weeks, then every 9 weeks. Overall survival- 12-weekly.
4. Efficacy assessments: in Part B2-Every 6 weeks (±7 days) (from 1st dose for A2, randomization for B2) for 18 weeks, then every 9 weeks (±7 days). Overall survival- 12-weekly.
5. Archival tumour (or biopsy)- at screening. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Not randomized for parts A1, A2 A3 and B1 / Randomized for part B2 |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| United Kingdom |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 14 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 35 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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