Clinical trial NCT05797168: Phase I/IIa Study of AZD5335 as Monotherapy and Combination Therapy in Participants With Solid Tumors
Official title: A Modular Phase I/IIa, Open-label 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Ovarian Cancer
Lung Adenocarcinoma
Keywords: ADC
PARP inhibitor
AZD5335
AZD5305
Saruparib
Bevacizumab
Carboplatin
Ovarian Cancer
Lung Adenocarcinoma
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-04-04
Enrollment: 396
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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 saruparib)
* Module 3 (AZD5335 in combination with bevacizumab)
* Module 4 (AZD5335 in combination with carboplatin +/- bevacizumab)
Primary purpose: TREATMENT

Brief summary: 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: 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: Core 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.
* 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,

  1. A previously irradiated lesion can be considered a target lesion if the lesion is progressing and well defined.
  2. 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) Male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus an additional contraceptive method) 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.

(ii) (ii) Sex and Contraceptive/Barrier Requirements: Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) \[(periodic abstinence e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception\], a vasectomized partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo Provera™ injections, oral contraceptive associated with inhibition of ovulation, and Evra Patch™, Xulane™, or NuvaRing®.

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 \[NCI\] 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-hepatitis B virus core protein (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 electrocardiograms (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 gastrointestinal 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 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), 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

Primary outcomes:
measure: Number of participants with adverse events/serious adverse events
timeFrame: From time of Informed Consent to 30 days post last dose.
measure: The number of participants with dose limiting toxicity(DLT), as defined in the protocol
timeFrame: 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 outcomes:
measure: Objective Response Rate (ORR)
timeFrame: From time of Informed Consent to progressive disease or withdrawal of consent.(approx 2 years)
measure: Duration of Response (DoR)
timeFrame: From the first documented response to confirmed progression or death in the absence of disease progression.(approx 2 years)
measure: Disease Control Rate (DCR)
timeFrame: From time of Informed Consent until progression.(approx 15 weeks)
measure: Progression free Survival (PFS)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: From time of first dose of AZD5335 or AZD5305 until death due to any cause.(approx 2 years)
measure: Module 1: Pharmacokinetics of AZD5335: Area Under the concentration-time curve(AUC)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335(approximately 12 weeks)
measure: Module 1: Pharmacokinetics of AZD5335: Maximum plasma concentration of the study drug (Cmax)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
measure: Module 1: Pharmacokinetics of AZD5335: Time to maximum plasma concentration of the study drug (T-max)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
measure: Module 1: Pharmacokinetics of AZD5335: Clearance
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
measure: Module 1: Pharmacokinetics of AZD5335: Terminal elimination half-life (t 1/2)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
measure: Immunogenicity of AZD5335
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5535.(approx 2 years)
measure: Module 1: To investigate baseline and on treatment changes in target expression.
timeFrame: Baseline and predicted intervals throughout the administration of AZD5335(approx 2 years)
measure: Module 2: Pharmacokinetics of AZD5335 and AZD5305 when given in combination.
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and AZD5305.(approx 12 weeks)
measure: Module 2, 3, and 4: Area Under the concentration-time curve (AUC)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 2, 3, and 4: Maximum plasma concentration of the study drug (Cmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 2, 3, and 4: Time to maximum plasma concentration of the study drug (T-max)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 2, 3, and 4: Clearance
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 2, 3, and 4: Terminal elimination half-life (t 1/2)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
measure: Module 3: Pharmacokinetics of AZD5335 and bevaczizumab when given in combination.
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and bevacizumab.(approx 12 weeks)
measure: Module 4: Pharmacokinetics of AZD5335 and carboplatin (+/- bevacizumab) when given in combination.
timeFrame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and carboplatin (+/- bevacizumab).(approx 12 weeks)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Irvine
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Providence
country: United States
facility: Research Site
state: Rhode Island
city: Providence
country: United States
facility: Research Site
state: Rhode Island
city: Houston
country: United States
facility: Research Site
state: Texas
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Liverpool
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: London
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Montréal
country: Canada
facility: Research Site
state: Quebec
city: Chengdu
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: Regensburg
country: Germany
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Hidaka-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Glasgow, Scotland
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: UT MD Anderson Cancer Center
name: Funda Meric-Bernstam, MD
role: PRINCIPAL_INVESTIGATOR
References: