A Phase 1 Study to Investigate Axatilimab Alone or in Combination With Durvalumab in Patients With Solid Tumors

A Phase 1 dose escalation study to determine if axatilimab as monotherapy and axatilimab in combination with a fixed dose of durvalumab will be sufficiently safe and well-tolerated at biologically active doses to warrant further investigation in patients with solid tumors.

This is an open label, multi-center Phase 1 study consisting of Phase 1a and Phase 1b. The study will evaluate axatilimab monotherapy (in Phase 1a) and axatilimab combined with durvalumab (in Phase 1b) in patients with advanced solid tumors which must have progressed following prior treatment and have no standard therapy alternatives left (i.e., patients must not be candidates for regimens known to provide clinical benefit). The primary objective will be to determine the MTD and/or RP2D of axatilimab as monotherapy (Phase 1a) and in combination with durvalumab (Phase 1b) as evaluated by the incidence of AEs that are defined as DLTs. In both study phases, a standard "3+3" dose escalation schema will be used to determine an MTD with 3-6 evaluable patients enrolled per dose level. The RP2D will be determined based on data from the dose escalation patients as reviewed by the Safety Review Committee (SRC; comprised of investigators and the Sponsor).

Eligibility Criteria:
INCLUSION CRITERIA:

Inclusion Criteria for Phase 1a and Phase 1b

Patients meeting all of the following criteria are considered eligible to participate in the study:

1. Signed written informed consent form (ICF).
2. Male or female patients aged ≥18 years.
3. Patients with histopathologically confirmed unresectable, recurrent, locally advanced, or metastatic solid tumors, with evaluable disease and must have progressed following prior treatment and have no standard therapy alternatives left (i.e., patients must not be candidates for regimens known to provide clinical benefit).
4. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at the study enrollment.
5. Has adequate organ and bone marrow function within 21 days before enrollment as defined below:

   a. Hematological laboratory values: i. Absolute Neutrophil Count (ANC) ≥1.5 × 10\^9/L ii. Platelets ≥100 × 10\^9/L iii. Hemoglobin ≥9 g/dL b. Renal laboratory values: i. Creatinine ≤1.5 times the Upper Limit of Normal (ULN) OR ii. Measured or calculated (per institutional standard) creatinine clearance (CrCl) ≥60 mL/min according to the Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local institutional standard measure) for patient with creatinine level \> 1.5 times institutional ULN.

   iii. Glomerular filtration rate may be used instead of creatinine or CrCl. c. Hepatic laboratory values: i. Total bilirubin ≤1.5 times ULN or ii. Direct bilirubin ≤ULN for patients with total bilirubin \>1.5 times ULN iii. AST and ALT ≤2.5 times ULN d. Creatine kinase ≤ ULN
6. Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade ≤1 (except alopecia) per NCI CTCAE v5.0 If a patient underwent major surgery or radiation therapy of \>30 Gray, the patient must have recovered from the toxicity and/or complications from the intervention.

   Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

   * Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
   * Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
8. Female patients of childbearing potential who are not abstinent and intend to be sexually active with a nonsterilized male partner must use at least 1 highly effective method of contraception (Table 11) from the time of screening throughout the total duration of the study drug treatment and 90 days after the last dose of study drug. Non-sterilized male partners of a female patient of childbearing potential must use male condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female patients should also refrain from breastfeeding throughout this period.
9. Non-sterilized male patients who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the study drug treatment and 90 days after the last dose of study drug. However, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period.
10. Must have a life expectancy of at least 12 weeks.

Additional Inclusion Criteria for Phase 1b 11. Body weight \> 30 kg 12. No prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.

EXCLUSION CRITERIA:

Exclusion Criteria for Phase 1a and Phase 1b

Patients meeting any of the following criteria are not eligible for study participation:

1. Diagnosis of immunodeficiency or receiving systemic corticosteroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug.

   a. Exceptions: 1) The use of physiologic doses of corticosteroids (i.e., ≤10 mg per day of equivalent prednisone) is allowed; 2) Steroids with no or minimal systemic effect (topical, inhalation) are allowed; 3) Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment; (4) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
2. Previously treated with a CSF-1, CSF-1R, and/or IL-34-blocking agents
3. Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
4. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the patient's best interest to participate, in the opinion of the treating Investigator, including, but not limited to:

   1. Active or prior documented autoimmune or inflammatory disorders (see Appendix 3 for complete list).
   2. History of active primary immunodeficiency
   3. Known active or latent tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).
   4. Myocardial infarction or arterial thromboembolic events within 6 months prior to enrollment or severe or unstable angina, New York Heart Association (NYHA) (see Appendix 2) Class III or IV disease, or a QTc interval \> 470 msec. History of QTc prolongation, ventricular fibrillation, ventricular tachycardia or Torsades de Pointes (TdP).
   5. Symptomatic congestive heart failure, cardiac arrhythmia, uncontrolled hypertension or diabetes mellitus.
   6. Active infection requiring systemic therapy.
   7. Interstitial lung disease
   8. Serious chronic gastrointestinal conditions associated with diarrhea
   9. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging (please see Appendix A (RECIST)) for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10 mg/day of prednisone or its equivalent for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at baseline.
5. Received a live attenuated vaccine within 30 days of the first dose of study drug.

   Note: Patients, if enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug.
6. Administration of colony stimulating factors (including granulocyte-colony stimulating factor \[G-CSF\], granulocyte macrophage-colony stimulating factor \[GM-CSF\], or recombinant erythropoietin) within 4 weeks prior to the first dose of study drug treatment.
7. 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
8. Received chemotherapy, anti-cancer mAb, targeted small molecule or other systemic anti-cancer therapy within 4 weeks of the first dose of study drug. However, patients receiving conventional and investigational small molecule targeted therapies that are not expected to have delayed toxicities may enter the study 5 half-lives or 28 days after the last dose of the compound, whichever is shorter.
9. Currently receiving treatment with any other agent listed on the prohibited medication list.
10. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
11. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid \[qualitative\]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBc Ab\] and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
12. Known alcohol or drug abuse.
13. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
14. Legal incapacity or limited legal capacity.
15. Evidence of muscle disorders or muscle injury that are known to cause serum creatine kinase (CK) elevation
16. Current pneumonitis or has a history of (non-infectious) pneumonitis that required steroids
17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
18. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study drug. Note: Local surgery of isolated lesions for palliative intent is acceptable.
19. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks or palliative radiation therapy within 2 weeks of the first dose of study drug
20. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study drug

    Additional Exclusion Criteria for Phase 1b
21. History of allogenic organ transplantation.
22. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4.