Phase I/IIa Study for AZD5335 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Solid Tumors

Study Overview
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Brief Summary
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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

Detailed Description
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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

Official Title
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FONTANA: A Modular Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Ascending Doses of AZD5335 Monotherapy and in Combination With Anti-cancer Agents in Participants With Solid Tumors

Conditions
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Ovarian Cancer, Lung Adenocarcinoma

Intervention / Treatment
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* Drug: AZD5335
* Drug: AZD5305


Participation Criteria
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Eligibility Criteria
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Core Inclusion Criteria: Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form 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. Consent to provide adequate baseline tumor sample, as applicable per module-specific criteria. Participant must be ≥ 18 years at the time of signing the informed consent. Willing to provide archival or baseline tumor sample. For participants who have previously received targeted therapies such as ADCs, a fresh baseline biopsy will be required. 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, A previously irradiated lesion can be considered a target lesion if the lesion is progressing and well defined. For participants who undergo biopsies at screening and/or on treatment, it is preferred though not required, that the biopsied lesion, be distinct from any target lesion used in the RECIST v1.1 evaluation. 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. (a) Male participants: (i) Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus spermicide, if available) post-screening through 5 half-lives (45 days) plus 6 months (approximately 7.5 months) following the last dose of study intervention. It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period. In addition, male participants must refrain from sperm donation while on study and for 5 half lives (45 days) plus 6 months ( 7.5 months) following the last dose of study intervention. (b) Female participants: (i) Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study intervention and a negative urine or serum pregnancy test prior to starting their next cycle of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly), from enrolment throughout the study and for 5 half-lives (45 days) plus 6 months (In total, 7.5 months) following the last dose of study intervention. It is strongly recommended for the male partner of a female participants to also use male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. In addition, female participants must refrain from egg donation while on study and for 5 half-lives (45 days) plus 6 months ( 7.5 months) following the last dose of study intervention. Core 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] Common Terminology Criteria for Adverse Events [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. 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). Patients with a past or resolved HBV/HCV infection are eligible if: (a) Negative for HBsAg and positive for anti-HBc or (b) Are 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 AST/ALT <3 × 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. Note for Japan: Japanese patients with positive anti-HBs/anti-HBc and negative HBsAg will be assessed following local guidelines. (c) 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 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 with low potential risk for recurrence. Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated carcinoma in situ without evidence of disease. Localized non-invasive 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); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. 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 cardiomyopathy. Severe valvular heart disease. Mean resting QTcF > 470 msec obtained from triplicate ECGs and averaged, recorded within 5 minutes. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. Uncontrolled intercurrent illness within 12 months prior to screening, including but not limited to serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations 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 30 days 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), lactating, breastfeeding, or intend 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. **Other module specific criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: The study consists of individual modules, each evaluating the safety and tolerability of AZD5335 dosed as monotherapy or in combination with specific treatments. Module 1 (AZD5335 monotherapy) Module 2 (AZD5335 in combination with AZD5305)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: AZD5335 Monotherapy<br>AZD5335 Monotherapy | Drug: AZD5335<br>* IV Antibody-drug conjugate<br>|
| Experimental: Module 2: AZD5335 + AZD5305<br>AZD5335 + AZD5305 | Drug: AZD5335<br>* IV Antibody-drug conjugate<br>Drug: AZD5305<br>* Oral PARP inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 if every 3 week dosing is tested or 28 days if every 4 weeks dosing is explored) | 

Secondary Outcome Measures

| Outcome Measure | 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) | 
| Pharmacodynamics of AZD5335 | The pharmacodynamics of AZD5335 by assessing changes in peripheral blood including, but not limited to cytokines, CA-125 and ctDNA. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335(approx 2 years) | 
| 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 warhead. | From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and AZD5305.(approx 12 weeks) | 
| Module 2: 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: 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: 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: 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: 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADC, PARP inhibitor, AZD5335, AZD5305, Ovarian Cancer, Lung Adenocarcinoma