Overview

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

Eligibility

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,
  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) 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