This is an open-label, multicenter, Phase 1a study to evaluate the safety, tolerability, PK
and preliminary efficacy of AN2025 and AN0025 in double or triple combination treatments with
Atezolizumab in patients with locally advanced/metastatic tumors.
1. Age ≥18 years at the time of informed consent and have provided signed informed
consent for the trial.
2. Willing and able to comply with all aspects of the protocol.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. Life expectancy ≥3 months.
5. Diagnosed with histologically confirmed locally advanced and nonresectable, or
6. Have received at least one line of prior systemic therapy or no alternative therapy to
prolong survival exists.
7. Have received no more than 4 prior lines of systemic therapy for advanced disease.
Prior therapy in an adjuvant or neoadjuvant setting is not considered as a prior line
of systemic therapy.
8. Have measurable disease per RECIST 1.1 as assessed by the local site investigator
and/or radiologist. Lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions.
9. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
of a tumor lesion not previously irradiated. If previously treated with
anti-PD-1/PD-L1 therapy, tumor tissue sample obtained following the most recent
anti-PD-1/PD-L1 therapy is required. Formalin-fixed, paraffin embedded (FFPE) tissue
blocks are preferred to slides. Newly obtained biopsies are preferred to archived
10. Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or
multiple gated acquisition (MUGA) scan.
11. Patient has organ function as shown by the following:
1. Absolute neutrophil count (ANC) ≥1.5 x 109/L.
2. Hemoglobin ≥9 g/dL (which may be reached by transfusion 2 weeks prior to the
start of the study treatment).
3. Platelets ≥100 x 109/L (which may be reached by transfusion).
4. International normalized ratio (INR) ≤1.5.
5. Calcium (corrected for serum albumin) within normal limits (WNL) or ≤ grade 1
severity according to NCI-CTCAE version 5.0 if judged clinically not significant
by the Investigator. Patients concomitantly taking bisphosphonates or denosumab
for calcium correction are eligible. (only applicable to Observations I and III)
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x upper
limit of normal (ULN) or <5.0 x ULN if liver metastases are present.
7. Total serum bilirubin ≤ ULN or ≤1.5 x ULN if liver metastases are present; or
total bilirubin ≤3.0 x ULN with direct bilirubin below or within normal range in
patients with well documented Gilbert's Syndrome. Gilbert's syndrome is defined
as presence of episodes of unconjugated hyperbilirubinemia with normal results
from cells blood count (including normal reticulocyte count and blood smear),
normal liver function test results, and absence of other contributing disease
processes at the time of diagnosis.
8. Serum creatinine ≤1.5 x ULN or calculated or directly measured creatinine
clearance (CrCL) >30 mL/min.
9. HbA1c ≤8%. (Only applicable to Observations I and III)
12. A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential Women are considered post-menopausal and
not of child-bearing potential if they have had 12 months of natural
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age
appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) at least six weeks prior to
Screening. In the case of oophorectomy alone, only when the reproductive status
of the woman has been confirmed by follow-up hormone level assessment, is she
considered not of child-bearing potential.
2. Woman of childbearing potential who agrees to follow contraceptive guidance
during the treatment period and for at least 5 months after the last dose of
Highly effective contraception is defined as either:
- Total abstinence: When this is in line with the preferred and usual lifestyle of
the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal,
post-ovulation methods] and withdrawal are not acceptable methods of
- Female sterilization: When the female study patient has had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks
before taking study treatment. In case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow-up hormone level
- Male partner sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate). For female study patients, the
vasectomized male partner should be the sole partner for that patient.
- Using a combination of any two of the following:
- Placement of an intrauterine device (IUD) or intrauterine system (IUS), and
- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
- Hormonal contraception methods (e.g., oral, injected, implanted).
13. A male participant must agree to use contraception during the treatment period and for
at least 5 months after the last dose of Atezolizumab.
1. Have been discontinued treatment due to a Grade 3 or higher immune-related AE (irAE)
from prior anti-PD-1or anti-PD-L1, or with an agent directed to another stimulatory or
co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
2. Have received prior systemic anti-cancer therapy including investigational agents
within 4 weeks or 5 half-lives, whichever is shorter.
Note: Participants must have recovered from all AEs due to previous therapies to ≤
Grade 1 or returned to baseline. Participants with ≤ Grade 2 neuropathy or alopecia
may be eligible.
3. Have received prior palliative radiotherapy within 2 weeks of start of study
treatment. Participants must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous
system (CNS) disease.
4. Severe, uncontrolled tumor-related pain.
5. Have received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Non live
COVID vaccinations or boosters should not occur during Cycle 1 or within 30 days prior
to the first dose of study drug.
6. Are currently participating in a study of an investigational agent or have used an
investigational device within 4 weeks prior to the first dose of study treatment.
Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been at least 4 weeks after the last dose of the
previous investigational agent (see Number 2 above).
7. Have had an allogenic tissue/solid organ transplant.
8. Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study drug.
9. With a history of another primary malignancy within the past 2 years, with the
exception of basal or squamous cell skin cancer, or carcinoma in situ of the cervix or
breast that has undergone potentially curative therapy.
10. Have known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment.
11. Have known severe hypersensitivity to study treatment components.
12. Have an active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)
is not considered a form of systemic treatment and is allowed. Have a history of
(non-infectious) pneumonitis that required steroids or have current pneumonitis.
13. Have a history of (non-infectious) pneumonitis that required steroids or have current
14. Have an active infection requiring systemic therapy within 2 weeks prior to Day 1 of
15. Participants with known human immunodeficiency virus (HIV) and/or history of Hepatitis
B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis
B virus (HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a
known positive Hep C Ab result and known quantitative HCV RNA results greater than the
lower limits of detection of the assay.
16. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,
unstable angina, myocardial infarction, or stroke within 6 months of the first dose of
study drug; or cardiac arrhythmia requiring medical treatment (including oral
17. Major surgery within 4 weeks before the first dose of study drug. Note: If participant
received major surgery, they must have recovered adequately from surgery and the
toxicity and/or complications requiring the intervention prior to starting study
18. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled
gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the
oral bioavailability of the investigational drugs.
19. Have a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in the best
interest of the participant to participate, in the opinion of the treating
20. Have a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study, e.g. history of
or active major depressive episode, bipolar disorder, obsessive-compulsive disorder,
schizophrenia, or history of suicidal attempt or ideation, homicidal ideation (e.g.,
risk of doing harm to self or others), or patients with active severe personality
disorders (defined according to Diagnostic and Statistical Manual of Mental Disorders
[DSM V]) are not eligible. Note: For patients with psychotropic treatments ongoing at
baseline, the dose and the schedule should not be modified within the previous six
weeks prior to start of study drug.
21. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 5 months
after the last dose of Atezolizumab.
22. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures >/=1 time per month.
23. Leptomeningeal disease.
24. Spinal cord compression not definitively treated with surgery and/or radiation, or
previously diagnosed and treated but without evidence that disease has been clinically
stable for >/=2 weeks prior to Day 1 of Cycle 1.
25. Oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1 for an active
infection (prophylactic antibiotic dosing that is deemed to be essential by the
investigator is allowed).
26. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
27. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or to any component of the atezolizumab formulation.
28. Active tuberculosis.
29. Patient has received previous treatment with any protein kinase B (PKB/AKT), mammalian
target of rapamycin (mTOR) inhibitors, or phosphatidylinositol 3 kinase (PI3K) pathway
inhibitors (only applicable to Observations I and III).
30. Patient has grade ≥2 neuropathy, colitis, pneumonitis, elevated HbA1C, and
uncontrolled endocrinopathies (e.g., hypothyroidism) from previous treatment (only
applicable to Observations I and III).
31. Have clinically manifest diabetes mellitus (DM) (treated and/or with clinical signs)
that is not well controlled (only applicable to Observations I and III).
32. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant, or
anti-Xa agents, for treatment, prophylaxis, or otherwise. Therapy with heparin, low
molecular weight heparin (LMWH), fondaparinux or novel oral anticoagulants (NOACs) is
33. Have diarrhea ≥2 CTCAE Grade 2 (only applicable to Observations I and III).
34. Patient is currently being treated with drugs known to be moderate and strong
inhibitors or inducers of isoenzyme CYP3A4, and the treatment cannot be discontinued
or switched to a different medication prior to starting study drug (only applicable to
Observations I and III). UGT inducers or inhibitors such as atazanavir, probenecid,
valproic acid, mefenamic acid, quinidine (only applicable to Observation II).
35. Patient has a history of non-compliance to any medical regimen or inability to grant
36. Patient that is currently receiving NSAIDs.
37. Patient that is currently receiving angiotensin converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs): Patients on these hypertensives at study
entry should be switched to other hypertensives prior to study drug dosing.