| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed platinum resistant small-cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To assess efficacy of intervention in terms of objective response with berzosertib + topotecan |
|
| E.2.2 | Secondary objectives of the trial |
-To assess efficacy of intervention in terms of duration of response with berzosertib + topotecan
- To assess efficacy of intervention in terms of PFS with berzosertib + topotecan
- To assess efficacy of intervention in terms of OS with berzosertib + topotecan followed by subsequent therapy
- To evaluate the safety and tolerability of berzosertib + topotecan
- To collect plasma concentration data via sparse PK sampling to contribute to population PK and exposure-response analyses of efficacy and safety of berzosertib and topotecan (and associated metabolites).
- To investigate the relationship between exposure of berzosertib and QTc
- To evaluate molecular and morphological biomarkers of response in tumor tissue and in plasma during berzosertib + topotecan
- To identify germline genetic polymorphisms that may be predictive of differences in the berzosertib + topotecan PK and efficacy (PGx).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are ≥ 18 years of age at the time of signing the informed consent. Type of Participant and Disease Characteristics
2. Histologically confirmed SCLC
3. Radiologically confirmed progression after first-line or chemoradiation platinum-based
treatment (carboplatin or cisplatin), with or without immunotherapy, for treatment of limited
or extensive stage SCLC, with a PFI < 90 days. The PFI is measured by the elapsed time
from the last day of the regimen of a platinum-based treatment until the first day of
documented disease progression
4. Measurable disease according to RECIST 1.1 at Screening. Evidence of measurable disease
must be confirmed by the IRC prior to start of treatment
5. Tumor tissue provision: archival (collected within 12 months before date of informed consent
form [ICF]) signature for Screening) or fresh biopsy specimen, if medically feasible
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2 and Karnofsky
Scale ≥ 60% (see Appendix 8)
7. Have adequate hematologic function as indicated by:
- Platelet count ≥ 100,000/mm3
- Hemoglobin ≥ 9.0 g/L. Prior red blood transfusions are allowed
- Absolute neutrophil count ≥ 1,500/μL with no growth factor treatment within 14 days of
obtaining the screening blood sample
- Total bilirubin level ≤ 1.5 × upper limit of normal (ULN), except in the case of known
Gilbert syndrome, in which case total bilirubin must be ≤ 2 ULN, an aspartate
aminotransferase (AST) and an alanine aminotransferase (ALT) level ≤ 3.0 × ULN or
≤ 5 × ULN in presence of liver metastases
-Adequate renal function defined as creatinine clearance ≥ 60 mL/min by calculation
using the Cockcroft-Gault formula or measured by 24-hour urine collection. The
Cockcroft-Gault formula is (l40 - age) × weight [kg]) / (72 × serum creatinine [mg/dL])
× 0.85 (if female)
Sex
8. Are male or female
9. Contraceptive use by males or females will be consistent with local regulations on
contraception methods for those participating in clinical studies
Male participants:
Agree to the following during the Study Intervention Period and for at least 6 months after the
last study intervention dose:
-Refrain from donating sperm
PLUS, either:
-Abstain from any activity that allows for exposure to ejaculate
OR
-Use a male condom: When having sexual intercourse with a woman of childbearing
potential (WOCBP), who is not currently pregnant, and advise her to use a highly
effective contraceptive method with a failure rate of < 1% per year, as described in
Appendix 3, since a condom may break or leak.
-Male participants must use a condom with pregnant female partners
Female participants:
Are not pregnant or breastfeeding, and at least 1 of the following conditions applies:
-Not a WOCBP
OR
-If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1%
per year), preferably with low user dependency, as described in Appendix 3 for the
following time periods:
o Before the first dose of the study intervention, if using hormonal contraception:
-Has completed at least one 4-week cycle of an oral contraception pill and either
had or has begun her menses
OR
-Has used a depot contraceptive or extended-cycle oral contraceptive for least
28 days and has a documented negative pregnancy test using a highly sensitive
assay
AND
A barrier method, as described in Appendix 3.
o During the Study Intervention Period
o After the Study Intervention Period (i.e., after the last study intervention dose is
administered) for at least 6 months after the last study intervention dose and agree
not to donate eggs (ova, oocytes) for reproduction during this period
The Investigator evaluates the effectiveness of the contraceptive method in relationship
to the first dose of study intervention.
o Have a negative serum pregnancy test, as required by local regulations, within
24 hours before the first study intervention dose.
Additional requirements for pregnancy testing during and after study intervention are in
Appendix 5.
Informed Consent
10. Capable of giving signed informed consent, as indicated in Appendix 2, which includes
compliance with the requirements and restrictions listed in the ICF and this protocol. |
|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. Clinically relevant (i.e., active), uncontrolled intercurrent illness including, but not limited to, severe active infection including, severe acute respiratory syndrome coronavirus-2 infection/coronavirus disease 2019, immune deficiencies, uncontrolled diabetes, uncontrolled arterial hypertension, symptomatic congestive heart failure (New York Heart Association Classification ≥ Class II), unstable angina pectoris, myocardial infarction, uncontrolled cardiac arrhythmia, cerebral vascular accident/stroke, or any psychiatric illness/social situations that would limit compliance with study requirements. The following exceptions apply:
a. Participants with human immunodeficiency virus infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction. Human immunodeficiency virus testing is not mandated for study inclusion. If performed, the participant must be consented for testing as per local standard guidance.
b. Participants with evidence of chronic hepatitis B virus (HBV) infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have ALT, AST, and total bilirubin levels < ULN, and provided there is no expected drug-drug interaction. Refer to the Schedule of Assessments (SoA; Table 1) for tests required at screening and during Study Intervention Period.
c. Participants with a history of hepatitis C virus (HCV) infection are eligible if they have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels < ULN. Refer to the SoA (Table 1) for tests required at screening and during Study Intervention Period.
2. Unstable brain metastases; however, participants with known brain metastases may be enrolled in this clinical study if they are clinically stable (without evidence of progression by imaging for at least 4 weeks prior to the first study intervention dose and any neurologic
symptoms have returned to baseline), have no evidence of new brain metastases, and are on a stable or decreasing dose of steroids for at least 14 days prior to study intervention. Participants with carcinomatous meningitis are excluded regardless of clinical stability. Screening central nervous system imaging is not mandatory
3. Prior malignant disease within the last 3 years. Exceptions include fully resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, in situ cervical cancer, fully resected ductal carcinoma in situ of the breast, superficial or noninvasive bladder cancer, and Stage IA, Grade I endometrioid endometrial cancer with no myometrial invasion, that has undergone curative therapy. Participants with other localized malignancies treated with curative intent need to be discussed with the Medical Monitor.
4. Participants not recovered from AEs Grade > 1 from prior anticancer therapies, including surgeries. Exception: Grade 2 AEs not constituting a safety risk (e.g., alopecia), based on the Investigator’s judgment; must consult with the medical Monitor prior to enrollment.
Prior/Concomitant Therapy
5. Two or more lines of prior systemic anticancer treatment, including retreatment with a platinum-based regimen
6. Prior treatment with topoisomerase I inhibitor, including topotecan and irinotecan
7. Prior treatment with an ATR inhibitor
8. Prior or concurrent treatment with a nonpermitted drug/intervention:
-Participants who may have received any of the following anticancer therapy(ies) within the following time windows from the first day of study interventions administration:
o Small molecule inhibitor therapy (including investigational) within 2 weeks or 5 half-lives, whichever is longer
o Any type of anticancer antibody or antibody drug conjugates within 4 weeks
o Systemic chemotherapy within 4 weeks (within 6 weeks for nitrosoureas/ mitomycin C)
o Prior curative-intent high-dose radiotherapy within 4 weeks. Prior palliative radiotherapy to metastatic lesion(s) is permitted provided it was completed at least 1 week prior to first day of study interventions administration and toxicities recovered to Grade ≤ 1.
o Any other type of anticancer therapy, not listed above, within 4 weeks.
-Concomitant use of strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)
enzymes that cannot be discontinued for at least 1 week prior to administration of study
intervention and for the duration of study intervention.
-Other prohibited concomitant medications as listed in Section 6.5.3.
Prior/Concurrent Clinical Study Experience 9. Concurrent participation in another interventional clinical study is not permitted. There are no restrictions on prior clinical study participation provided the above washout periods are followed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response according to RECIST 1.1 as assessed by the IRC Objective response according to RECIST 1.1 as assessed by the IRC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Objective response assessed by IRC during study |
|
| E.5.2 | Secondary end point(s) |
-Duration of response according to RECIST 1.1 as assessed by the IRC.
- Progression-free survival according to RECIST 1.1
- Overall survival
- Change from baseline in physical functioning measured by the EORTC QLQ-C30; cough, dyspnea, and chest pain measured by EORTC QLQ-LC13; health state as measured by VAS as a component of the EQ-5D-5L
- Occurrence of AEs and treatment-related AEs and occurrence of clinically significant changes in vital signs,
laboratory parameters and 12-lead ECG findings
- Change from baseline in functioning scales and symptom scales/items measured by EORTC QLQ-C30 and EORTC QLQ-LC13
- Time to deterioration in functioning scales and symptom scales/items
- Concentrations of berzosertib (berzosertib metabolites) and topotecan in plasma
- Relative changes from Baseline in ECG parameter QTc in relation to berzosertib plasma concentration
- Association of baseline and on treatment biomarkers with response to treatment
- Association of germline genetic polymorphisms as detected in normal blood DNA with berzosertib and
topotecan clinical efficacy.
- occurrence of DLTs in JPN participants.
- - OR and DOR
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- DOR and PFS: from first documentation of objective response to PD or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or first study intervention
- OS: from first study intervention to death
- QLQ questionnaires: throughout study
- AEs measured during study
. time to deterioration from first study intervention and first occurrence of worsening in HRQoL score
- Concentrations of berzosertib and topotecan in plasma at blood test timepoint.
- ECG par. all times after dosing with concurrent QTc and plasma concentration assessment
- Occurence of DLTs until end of Cycle 1 in JPN
- OR and DOR: from first documentation of objective response to PD or death, within 2 scheduled tumor assessments after last evaluable assessment or 1st intervention. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | No |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| China |
| Japan |
| United States |
| Belgium |
| France |
| Italy |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
Print
