Trial Information
Status:
Open
Specialty:
Gynaecological
Date Opened:
28/05/2026
Planned Close date:
-
Sponsors:
AstraZeneca AB - Sweden
Site Recruitment:
0 /
3
Principal Investigator:
Dr Sarah Moon
Study Title:
TREVI-OC-01
Contacts
Research Nurse / Study Coordinator:
Hilary Thatcher
Administrator:
-
A Randomised, Open-label, Phase III Study of AZD5335 Versus Mirvetuximab Soravtansine in FRα-high and AZD5335 Versus Investigator’s Choice Chemotherapy in FRα-low Expressing High-grade Platinum-resistant Epithelial Ovarian Cancer Patients (TREVI-OC-01)
A Randomised, Open-label, Phase III Study of AZD5335 Versus Mirvetuximab Soravtansine in FRα-high and AZD5335 Versus Investigator’s Choice Chemotherapy in FRα-low Expressing High-grade Platinum-resistant Epithelial Ovarian Cancer Patients (TREVI-OC-01)
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participants must be females ≥ 18 years of age (or the legal age of consent in the jurisdiction where the clinical trial is conducted) at the time of signing the informed consent form.
Type of Participant and Disease Characteristics
2. Participants with confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
3. Participants must have platinum-resistant disease:
a. Participants who have only had one prior line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date of the last dose of platinum.
b. Participants who have received 2 or 3 lines of platinum therapy must have progressed ≤ 6 months after the date of the last dose of platinum.
Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
Note: Participants who are platinum-refractory during front-line treatment are excluded (see Section 5.2 [Exclusion Criteria]).
4. Participants must have radiologically progressed on or after their most recent line of therapy.
5. Participants must have received at least one, but no more than 3, prior systemic lines of anti-cancer therapy, and must be those for whom single-agent therapy is appropriate as the next line of treatment:
a. Adjuvant ± neoadjuvant considered one line of therapy.
b. Prior treatment with bevacizumab is required if the participant is eligible per approved label and SoC institutional guidelines, except in cases of documented contraindication, precaution or intolerance.
c. Maintenance therapy (eg, bevacizumab, PARPi) will be considered as part of the preceding line of therapy (ie, not counted as a line of therapy).
d. Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (ie, not counted independently).
e. Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
6. Participants with documented BRCA mutation (germline and/or somatic) must have received prior PARPi if the participant is eligible per approved label and standard-of-care institutional guidelines, except in cases of documented contraindication, precaution or intolerance.
7. Participants must have an ECOG Performance Status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to randomisation.
8. Minimum life expectancy of 12 weeks at screening.
9. Provision at Screening 1 of an FFPE tumour tissue sample for central testing of FRα expression (see Section 8.7.1.1).
10. Participant’s tumour must have at least ≥ 25% of viable tumour cells with ≥ 1+ membrane staining intensity via central testing with the VENTANA FOLR1 (FOLR1-2.1) IUO IHC assay.
11. At least one measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline that can be accurately measured as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT (preferable) or MRI and is suitable for accurate repeated measurements.
12. Participants must have adequate organ and bone marrow function as follows:
• Haemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelet count ≥ 100 × 109/L
• Total bilirubin ≤ 1.5 × the ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia)
• ALT and AST ≤ 3 × ULN; for participants with hepatic metastases, ALT, and AST ≤ 5 × ULN
• Calculated CrCL ≥ 45 mL/min as determined by Cockcroft Gault (using actual body weight).
Cockcroft Gault formula for females:
CrCL (mL/min) = Weight (kg) × (140 - Age)
72 × serum creatinine (mg/dL) x 0.85
Note: Haematological criteria cannot be met with ongoing or recent blood product transfusions or growth factor support within 21 days prior to the scheduled first dose of study intervention.
Sex and Contraceptive/Barrier Requirements
13. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Females not of childbearing potential, see Appendix G for definition.
• Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for FOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation.
• FOCBP must use one highly effective form of contraception from enrolment throughout study and until at least 8 months following the last dose of study intervention; refer to Appendix G for further details.
Pregnancy test:
• All FOCBP must have a negative serum pregnancy test result at Screening 2 (Visit 2).
Informed Consent
14. Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in the protocol. All participants must sign both the Screening 1 ICF and the main study ICF. The Screening 1 ICF will be provided for consent of mandatory FRα testing.
15. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional Genomics Initiative research that supports the Genomic Initiative (see Appendix D 2).
Age
1. Participants must be females ≥ 18 years of age (or the legal age of consent in the jurisdiction where the clinical trial is conducted) at the time of signing the informed consent form.
Type of Participant and Disease Characteristics
2. Participants with confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
3. Participants must have platinum-resistant disease:
a. Participants who have only had one prior line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date of the last dose of platinum.
b. Participants who have received 2 or 3 lines of platinum therapy must have progressed ≤ 6 months after the date of the last dose of platinum.
Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
Note: Participants who are platinum-refractory during front-line treatment are excluded (see Section 5.2 [Exclusion Criteria]).
4. Participants must have radiologically progressed on or after their most recent line of therapy.
5. Participants must have received at least one, but no more than 3, prior systemic lines of anti-cancer therapy, and must be those for whom single-agent therapy is appropriate as the next line of treatment:
a. Adjuvant ± neoadjuvant considered one line of therapy.
b. Prior treatment with bevacizumab is required if the participant is eligible per approved label and SoC institutional guidelines, except in cases of documented contraindication, precaution or intolerance.
c. Maintenance therapy (eg, bevacizumab, PARPi) will be considered as part of the preceding line of therapy (ie, not counted as a line of therapy).
d. Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (ie, not counted independently).
e. Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
6. Participants with documented BRCA mutation (germline and/or somatic) must have received prior PARPi if the participant is eligible per approved label and standard-of-care institutional guidelines, except in cases of documented contraindication, precaution or intolerance.
7. Participants must have an ECOG Performance Status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to randomisation.
8. Minimum life expectancy of 12 weeks at screening.
9. Provision at Screening 1 of an FFPE tumour tissue sample for central testing of FRα expression (see Section 8.7.1.1).
10. Participant’s tumour must have at least ≥ 25% of viable tumour cells with ≥ 1+ membrane staining intensity via central testing with the VENTANA FOLR1 (FOLR1-2.1) IUO IHC assay.
11. At least one measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline that can be accurately measured as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT (preferable) or MRI and is suitable for accurate repeated measurements.
12. Participants must have adequate organ and bone marrow function as follows:
• Haemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelet count ≥ 100 × 109/L
• Total bilirubin ≤ 1.5 × the ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia)
• ALT and AST ≤ 3 × ULN; for participants with hepatic metastases, ALT, and AST ≤ 5 × ULN
• Calculated CrCL ≥ 45 mL/min as determined by Cockcroft Gault (using actual body weight).
Cockcroft Gault formula for females:
CrCL (mL/min) = Weight (kg) × (140 - Age)
72 × serum creatinine (mg/dL) x 0.85
Note: Haematological criteria cannot be met with ongoing or recent blood product transfusions or growth factor support within 21 days prior to the scheduled first dose of study intervention.
Sex and Contraceptive/Barrier Requirements
13. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Females not of childbearing potential, see Appendix G for definition.
• Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for FOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation.
• FOCBP must use one highly effective form of contraception from enrolment throughout study and until at least 8 months following the last dose of study intervention; refer to Appendix G for further details.
Pregnancy test:
• All FOCBP must have a negative serum pregnancy test result at Screening 2 (Visit 2).
Informed Consent
14. Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in the protocol. All participants must sign both the Screening 1 ICF and the main study ICF. The Screening 1 ICF will be provided for consent of mandatory FRα testing.
15. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional Genomics Initiative research that supports the Genomic Initiative (see Appendix D 2).
Participants are excluded from the study if any of the following criteria apply:
1. Participants with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumours containing any of the above histologies, or low-grade or borderline ovarian tumour.
2. Primary platinum-refractory disease, defined as disease that did not respond to or has progressed ≤ 3 months after the last dose of first line platinum-containing chemotherapy.
Medical Conditions
3. Participants with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular oedema, macular degeneration, presence of papilledema, and/or monocular vision.
4. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, history of allogenic organ transplant) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
5. Current signs, symptoms, or clinical investigations consistent with bowel obstruction, including sub-occlusive disease.
6. History of another primary malignancy except for malignancy treated with curative intent and with no known active disease for at least 2 years prior to screening of study intervention and of low potential risk for recurrence. Exceptions include adequately treated non-melanoma skin cancer or lentigo maligna and curatively treated carcinoma in situ without evidence of disease and localised non-invasive primary disease under surveillance.
7. Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
Note: Participants with chronic, stable Grade ≤ 2 toxicities (with no worsening to Grade > 2 for 3 months prior to randomisation and managed with standard treatment) from previous anti-cancer therapy, such as peripheral neuropathy, fatigue, and endocrinopathies may be included.
8. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention, or a history of leptomeningeal carcinoma. A minimum of 28 days must have elapsed between the end of whole brain radiotherapy and study enrolment (refer to Appendix H 3 for further details on washout periods).
9. Known active infection with HBV (verified by known positive HBsAg result) or HCV. The following are exceptions:
a. Participants with a past or resolved HBV infection are eligible if negative for HBsAg and positive for anti-HBc and HBV DNA is negative (viral load < 100 IU/mL or below the detectable limit of the locally available test).
b. Participants who are HBsAg + with chronic HBV infection (lasting 6 months or longer) and meet conditions i to iii below:
i. HBV DNA viral load < 100 IU/mL or below the detectable limit of the locally available test.
ii. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 2.5 × ULN, which are not attributable to HBV infection.
iii. Start or maintain antiviral treatment for at least 2 weeks prior to study treatment if clinically indicated as per the investigator or as per local guideline.
c. Participants testing positive for HCV antibody are eligible only if the PCR test result is negative for HCV RNA.
10. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350/mm3 , no history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). Note: HIV testing only done if clinically indicated or required by local regulations or IRB/IEC.
11. Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
12. Participant has non-infectious ILD/pneumonitis or has a history of non-infectious ILD/pneumonitis that required oral or IV steroids or supplemental oxygen, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Examples of suspected ILD/pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as combined pulmonary fibrosis and emphysema (CPFE), and any radiographic features consistent with interstitial lung abnormalities, including but not limited to, extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing.
Note: Participants with a history of radiation pneumonitis which has clinically and radiologically resolved and not requiring treatment at the time of screening with steroids may be eligible. The investigator must carefully evaluate benefit-risk assessment on a case-by-case basis and discuss with the medical monitor prior to the participant’s enrolment.
13. Participant meets one or more of the following cardiovascular criteria:
• Uncontrolled hypertension (refractory to medical intervention).
• Mean resting QTcF > 470 ms, obtained from triplicate ECGs performed at screening.
• Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on investigator judgement with cardiologist consultation recommended.
• Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of screening.
• History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
• Other cardiovascular comorbidities including symptomatic heart failure (as defined by New York Heart Association class ≥ 2), prior or current cardiomyopathy, or severe uncorrected valvular heart disease.
Prior/Concomitant Therapy
14. Prior treatment with any FRα-targeted therapy, including MIRV, or any TOP1i ADC. For the following prior/concomitant therapies, refer to Appendix H 3 for definitions of adequate washout periods.
15. Prior exposure to nitrosourea, mitomycin C, chloroquine, or hydroxychloroquine without adequate treatment washout period before randomisation (Appendix H 3).
16. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumour embolisation, or monoclonal antibodies) without adequate washout period prior to the first dose of study intervention (eg, 21 days; Appendix H 3). If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca and the investigator. Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded, see Appendix H 2 and H 3.
17. Any concurrent anti-cancer treatment without an adequate washout period (eg, 21 days, if sufficient [Appendix H 3]). Concurrent use of hormonal therapy for non-cancer-related conditions (eg, HRT) is allowed.
18. Any investigational agents or study interventions from a previous clinical study without an adequate washout period (eg, 21 days; if sufficient [Appendix H 3]).
19. Palliative radiotherapy with a limited field of radiation within 14 days, or with wide field of radiation or to more than 30% of the bone marrow within 28 days, prior to the first dose of study intervention.
20. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
21. Medications or herbal supplements known to be strong inhibitors of CYP3A (Appendix H 2).
22. Substance abuse or any other medical conditions that would increase the safety risk of the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the investigator.
23. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
Note: Participants, if enrolled, should not receive live vaccine whilst receiving study intervention and until 3 months after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines.
Note: If a COVID-19 vaccine is administered it should be done > 72 hours prior to study intervention initiation.
Prior/Concurrent Clinical Study Experience
24. Participation in another clinical study with a study intervention administered in the last 12 months (unless the safety profile is known prior to first dose of study intervention), or concurrent enrolment in another clinical study (unless the study is observational or non interventional, or the participant is in the follow up period of an interventional study).
25. Previous enrolment in the present study.
26. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Other Exclusions
27. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
28. Participants with a known hypersensitivity to study intervention(s) or any of the excipients of the product(s).
29. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding or intention to become pregnant during the study period.
1. Participants with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumours containing any of the above histologies, or low-grade or borderline ovarian tumour.
2. Primary platinum-refractory disease, defined as disease that did not respond to or has progressed ≤ 3 months after the last dose of first line platinum-containing chemotherapy.
Medical Conditions
3. Participants with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular oedema, macular degeneration, presence of papilledema, and/or monocular vision.
4. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, history of allogenic organ transplant) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
5. Current signs, symptoms, or clinical investigations consistent with bowel obstruction, including sub-occlusive disease.
6. History of another primary malignancy except for malignancy treated with curative intent and with no known active disease for at least 2 years prior to screening of study intervention and of low potential risk for recurrence. Exceptions include adequately treated non-melanoma skin cancer or lentigo maligna and curatively treated carcinoma in situ without evidence of disease and localised non-invasive primary disease under surveillance.
7. Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
Note: Participants with chronic, stable Grade ≤ 2 toxicities (with no worsening to Grade > 2 for 3 months prior to randomisation and managed with standard treatment) from previous anti-cancer therapy, such as peripheral neuropathy, fatigue, and endocrinopathies may be included.
8. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention, or a history of leptomeningeal carcinoma. A minimum of 28 days must have elapsed between the end of whole brain radiotherapy and study enrolment (refer to Appendix H 3 for further details on washout periods).
9. Known active infection with HBV (verified by known positive HBsAg result) or HCV. The following are exceptions:
a. Participants with a past or resolved HBV infection are eligible if negative for HBsAg and positive for anti-HBc and HBV DNA is negative (viral load < 100 IU/mL or below the detectable limit of the locally available test).
b. Participants who are HBsAg + with chronic HBV infection (lasting 6 months or longer) and meet conditions i to iii below:
i. HBV DNA viral load < 100 IU/mL or below the detectable limit of the locally available test.
ii. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 2.5 × ULN, which are not attributable to HBV infection.
iii. Start or maintain antiviral treatment for at least 2 weeks prior to study treatment if clinically indicated as per the investigator or as per local guideline.
c. Participants testing positive for HCV antibody are eligible only if the PCR test result is negative for HCV RNA.
10. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350/mm3 , no history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). Note: HIV testing only done if clinically indicated or required by local regulations or IRB/IEC.
11. Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
12. Participant has non-infectious ILD/pneumonitis or has a history of non-infectious ILD/pneumonitis that required oral or IV steroids or supplemental oxygen, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Examples of suspected ILD/pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as combined pulmonary fibrosis and emphysema (CPFE), and any radiographic features consistent with interstitial lung abnormalities, including but not limited to, extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing.
Note: Participants with a history of radiation pneumonitis which has clinically and radiologically resolved and not requiring treatment at the time of screening with steroids may be eligible. The investigator must carefully evaluate benefit-risk assessment on a case-by-case basis and discuss with the medical monitor prior to the participant’s enrolment.
13. Participant meets one or more of the following cardiovascular criteria:
• Uncontrolled hypertension (refractory to medical intervention).
• Mean resting QTcF > 470 ms, obtained from triplicate ECGs performed at screening.
• Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on investigator judgement with cardiologist consultation recommended.
• Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of screening.
• History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
• Other cardiovascular comorbidities including symptomatic heart failure (as defined by New York Heart Association class ≥ 2), prior or current cardiomyopathy, or severe uncorrected valvular heart disease.
Prior/Concomitant Therapy
14. Prior treatment with any FRα-targeted therapy, including MIRV, or any TOP1i ADC. For the following prior/concomitant therapies, refer to Appendix H 3 for definitions of adequate washout periods.
15. Prior exposure to nitrosourea, mitomycin C, chloroquine, or hydroxychloroquine without adequate treatment washout period before randomisation (Appendix H 3).
16. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumour embolisation, or monoclonal antibodies) without adequate washout period prior to the first dose of study intervention (eg, 21 days; Appendix H 3). If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca and the investigator. Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded, see Appendix H 2 and H 3.
17. Any concurrent anti-cancer treatment without an adequate washout period (eg, 21 days, if sufficient [Appendix H 3]). Concurrent use of hormonal therapy for non-cancer-related conditions (eg, HRT) is allowed.
18. Any investigational agents or study interventions from a previous clinical study without an adequate washout period (eg, 21 days; if sufficient [Appendix H 3]).
19. Palliative radiotherapy with a limited field of radiation within 14 days, or with wide field of radiation or to more than 30% of the bone marrow within 28 days, prior to the first dose of study intervention.
20. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
21. Medications or herbal supplements known to be strong inhibitors of CYP3A (Appendix H 2).
22. Substance abuse or any other medical conditions that would increase the safety risk of the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the investigator.
23. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
Note: Participants, if enrolled, should not receive live vaccine whilst receiving study intervention and until 3 months after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines.
Note: If a COVID-19 vaccine is administered it should be done > 72 hours prior to study intervention initiation.
Prior/Concurrent Clinical Study Experience
24. Participation in another clinical study with a study intervention administered in the last 12 months (unless the safety profile is known prior to first dose of study intervention), or concurrent enrolment in another clinical study (unless the study is observational or non interventional, or the participant is in the follow up period of an interventional study).
25. Previous enrolment in the present study.
26. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Other Exclusions
27. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
28. Participants with a known hypersensitivity to study intervention(s) or any of the excipients of the product(s).
29. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding or intention to become pregnant during the study period.