Phase I/IIa Study of AZD5335 as Monotherapy and Combination Therapy in Participants With Solid Tumors
PHASE1PHASE2RECRUITING
This research is designed to determine if experimental treatment with Antibody-drug conjugate, AZD5335, alone, or in combination with anti-cancer agents is safe, tolerable, and has anti-cancer activity in patients with advanced tumors.
Study details:
This study is a Phase I/IIa modular, open-label, multi-center study of AZD5335 administered either as monotherapy or in combination with other anti-cancer agents in participants with advanced solid malignancies.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative. Participants who do not provide informed consent for Optional Genetic Research may still be enrolled in the study.
- Participant must be ≥ 18 years at the time of signing the informed consent.
- Willing to provide adequate archival and/or baseline tumor sample as applicable per module-specific criteria.
- For participants who have previously received targeted therapies such as ADCs, a fresh baseline biopsy will be required unless the most recent archival tissue sample was collected after receipt of such treatment.
- Eastern Cooperative Oncology Group Performance Status of 0 or 1.
- Participants with advanced solid tumors must have received prior adequate therapy in accordance with local practice for their tumor type and stage of disease, or, in the opinion of the Investigator, a clinical trial is the best option for the next treatment based on response and/or tolerability to prior therapy. Participants with contraindications or who refuse therapy in accordance with local practice may also be considered provided that it is documented that he/she was informed about all therapeutic options.
- Participants must have measurable disease per RECIST v1.1.
- Life expectancy ≥ 12 weeks.
- Adequate organ and marrow function.
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion criteria
- Patients with spinal cord compression or a history of leptomeningeal carcinomatosis.
- Patients with brain metastases unless, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to first dose of study intervention.
- Treatment with any of the protocol defined medications, without adequate washout periods or time before the first dose of study intervention.
- Unresolved toxicities of Grade ≥ 2 (National Cancer Institute [NCI] CTCAE v5.0) from prior therapy (excluding vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy). Participants with stable ≤ Grade 2 neuropathy are eligible.
- Active infection, including tuberculosis and infections with hepatitis B virus (HBV; verified by known positive hepatitis B surface antigen [HBsAg] result), hepatitis C virus (HCV) or known HIV infection that is not well controlled.
- Patients with a past or resolved HBV/HCV infection are eligible if: Negative for HBsAg and positive for anti-hepatitis B virus core protein (HBc) or HBsAg + with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: (i) HBV DNA viral load <100 IU/mL. (ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <3 x upper limit of normal (ULN), which are not attributable to HBV infection. (iii) Start or maintain antiviral treatment if clinically indicated as per the Investigator or as per local guideline.
- Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.
- Patient has 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.
- Patients with a history of radiation pneumonitis which has clinically and radiologically resolved and not requiring treatment with steroids may be eligible.
- History of another 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 with low potential risk for recurrence. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated carcinoma in situ without evidence of disease. Localized non-invasive solid organ primary disease under surveillance.
- Patients with any of the following cardiac criteria: History of arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, and ventricular tachycardia), which is symptomatic or requires treatment NCI CTCAE v5.0 Grade 3 except for: (i) Rate controlled asymptomatic atrial fibrillation. NOTE: significant abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, and magnesium) should be corrected before starting the study intervention.
- Uncontrolled hypertension.
- 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.
- Symptomatic heart failure (as defined by New York Heart Association class ≥ 2).
- Prior or current diagnosis of cardiomyopathy considered clinically relevant per investigator's judgement.
- Severe uncorrected valvular heart disease.
- Mean resting QTcF > 470 msec obtained from triplicate electrocardiograms (ECGs) and averaged, recorded within 5 minutes.
- Any factor that, in the opinion of the investigator, increases the proarrhythmic risk of QT prolongation, such as congenital long QT syndrome, family history of long QT syndrome, hypertrophic cardiomyopathy, or unexplained sudden cardiac death under 40 years of age.
- Uncontrolled and/or unresolved intercurrent illness within 12 months prior to screening, including but not limited to serious chronic gastrointestinal conditions associated with diarrhea, or illness (including psychiatric illness) and/or social situations, in the opinion of the investigator, that would limit compliance with study requirements and activities, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
- Substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
- 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 up to 3 months after the last dose of study intervention. Participants can receive Coronavirus (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 or after completion of the DLT period.
- For women only - currently pregnant (confirmed with positive pregnancy test or suspected), lactating, breastfeeding, or intention to become pregnant during the study period.
- Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow-up period of an interventional study.
- Patients with a known hypersensitivity to study intervention or any of the excipients of the product.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
- Previous enrolment in the present study.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE1PHASE2
Study ID
NCT05797168
Intervention or treatment
DRUG: AZD5335
DRUG: Saruparib (AZD5305)
DRUG: Bevacizumab
DRUG: Carboplatin
DRUG: AZD9574
Conditions
- Ovarian Cancer
- Lung Adenocarcinoma
- Endometrial Cancer
- Lung Squamous Cell Carcinoma
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Research sites nearby
Closest Location:
Research Site
Select from list below to view details:
Research Site
Liverpool, Australia
Research Site
Melbourne, Australia
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Who is running the clinical trial?
A
AstraZeneca
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Module 1: Torvu-sam Monotherapy
| Drug: Torvutatug samrotecan |
EXPERIMENTAL: Module 2: Torvu-sam + Saruparib
| Drug: Torvutatug samrotecan, Drug: Saruparib |
EXPERIMENTAL: Module 3: Torvu-sam + Bevacizumab
| Drug: Torvutatug samrotecan, Drug: Bevacizumab |
EXPERIMENTAL: Module 4: Torvu-sam + Carboplatin +/- Bevacizumab
| Drug: Torvutatug samrotecan, Drug: Bevacizumab, Drug: Carboplatin |
EXPERIMENTAL: Module 5: Torvu-sam + Palacaparib +/- Bevacizumab
| Drug: Torvutatug samrotecan, Drug: Bevacizumab, Drug: Palacaparib |
EXPERIMENTAL: Module 6: Torvu-sam + Pembrolizumab +/- Palacaparib
| Drug: Torvutatug samrotecan, Drug: Palacaparib, Drug: Pembrolizumab |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with adverse events/serious adverse events | Number of participants with incidence of adverse events and with serious adverse events including changes from baseline in laboratory parameters, vital signs, ECGs, and physical examination. | From time of Informed Consent to 30 days post last dose. |
| The number of participants with dose limiting toxicity(DLT), as defined in the protocol | A DLT is defined as any ≥ Grade 3 treatment-emergent AE that occurs during the DLT evaluation period, not attributable to the underlying disease or extraneous causes (as defined in the protocol) | From the first dose of AZD5335 on Cycle 1 Day 1 up to and including the planned end of Cycle 1 (At the end of 21 days) |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Objective Response Rate (ORR) | The percentage of participants with a confirmed CR or PR according to RECIST v1.1 criteria. | From time of Informed Consent to progressive disease or withdrawal of consent.(approx 2 years) |
| Duration of Response (DoR) | The time from the date of first response until date of disease progression or death in the absence of disease progression. | From the first documented response to confirmed progression or death in the absence of disease progression.(approx 2 years) |
| Disease Control Rate (DCR) | The percentage of participants who have a best objective response of confirmed CR or PR or who have SD for at least 15 weeks after start of treatment (to allow for an early assessment within the assessment window). | From time of Informed Consent until progression.(approx 15 weeks) |
| Progression free Survival (PFS) | Progression-free survival is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participant withdraws from assigned therapy or receives another anti-cancer therapy prior to progression. Participants who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST v1.1 assessment | From time of first dose of AZD5335 or AZD5305 until the date of objective disease progression or death (by any cause in the absence of progression).(approx 2 years) |
| Overall Survival (OS) | The time until death due to any cause. | From time of first dose of AZD5335 or AZD5305 until death due to any cause.(approx 2 years) |
| Module 1: Pharmacokinetics of AZD5335: Area Under the concentration-time curve(AUC) | Area under the plasma concentration-time curve | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335(approximately 12 weeks) |
| Module 1: Pharmacokinetics of AZD5335: Maximum plasma concentration of the study drug (Cmax) | Maximum observed plasma concentration of the study drug | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks) |
| Module 1: Pharmacokinetics of AZD5335: Time to maximum plasma concentration of the study drug (T-max) | Time to maximum observed plasma concentration of the study drug | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks) |
| Module 1: Pharmacokinetics of AZD5335: Clearance | A pharmacokinetic measurement of the volume of plasma from which the study drug is completely removed per unit time. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks) |
| Module 1: Pharmacokinetics of AZD5335: Terminal elimination half-life (t 1/2) | Terminal elimination half life. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks) |
| Immunogenicity of AZD5335 | The number and percentage of participants who develop ADAs. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5535.(approx 2 years) |
| Module 1: To investigate baseline and on treatment changes in target expression. | The clinical activity by baseline and on-treatment changes in tumor target expression. | Baseline and predicted intervals throughout the administration of AZD5335(approx 2 years) |
| Module 2: Pharmacokinetics of AZD5335 and AZD5305 when given in combination. | The plasma concentrations of AZD5335, total antibody, and total unconjugated payload. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and AZD5305.(approx 12 weeks) |
| Module 2, 3, 4, and 5: Area Under the concentration-time curve (AUC) | Area under the plasma concentration-time curve | At predefined intervals throughout the treatment period (approximately 12 weeks) |
| Module 2, 3, 4, and 5: Maximum plasma concentration of the study drug (Cmax) | Maximum observed plasma concentration of the study drug | At predefined intervals throughout the treatment period (approximately 12 weeks) |
| Module 2, 3, 4, and 5: Time to maximum plasma concentration of the study drug (T-max) | Time to maximum observed plasma concentration of the study drug | At predefined intervals throughout the treatment period (approximately 12 weeks) |
| Module 2, 3, 4, and 5: Clearance | A pharmacokinetic measurement of the volume of plasma from which the study drug is completely removed per unit time. | At predefined intervals throughout the treatment period (approximately 12 weeks) |
| Module 2, 3, 4, and 5: Terminal elimination half-life (t 1/2) | Terminal elimination half life. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks) |
| Module 3: Pharmacokinetics of AZD5335 and bevaczizumab when given in combination. | The plasma concentrations of AZD5335, total antibody, and total unconjugated payload. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and bevacizumab.(approx 12 weeks) |
| Module 4: Pharmacokinetics of AZD5335 and carboplatin (+/- bevacizumab) when given in combination. | The plasma concentrations of AZD5335, total antibody, and total unconjugated payload. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and carboplatin (+/- bevacizumab).(approx 12 weeks) |
| Module 5: Pharmacokinetics of AZD5335 and AZD9574 when given in combination. | The plasma concentrations of AZD5335, total antibody, and total unconjugated payload. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and AZD9574.(approx 12 weeks) |
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References
Clinical Trials Gov: Phase I/IIa Study of AZD5335 as Monotherapy and Combination Therapy in Participants With Solid TumorsOther trials to consider
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