This trial is a phase 1/1b study to evaluate the safety, efficacy, and tolerability of
APX005M in combination with nivolumab and cabiralizumab.
The phase 1 dose escalation portion of the study will enroll patients with advanced solid
tumors melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) in 6
cohorts to determine the recommended phase II dose (RP2D) of APX005M.
The phase 1b dose expansion portion will study the triple drug combination separately in the
three disease cohorts: melanoma, NSCLC, and RCC.
Must have one of the following diagnoses:
Melanoma: Unresectable stage III or stage IV melanoma, irrespective of BRAF status, with
histologic or cytologic confirmation.
RCC: Histologic or cytologically documented, locally advanced unresectable or metastatic
RCC irrespective of histologic subtype
NSCLC: Histologic or cytologically documented, locally advanced or metastatic (i.e. Stage
IIIB not eligible for definitive chemoradiotherapy, stage IV, or recurrent) NSCLC. Patients
known to harbor an ALK rearrangement or EGFR mutation known to be sensitive to FDA-approved
tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression
(during or after treatment) or intolerance to an FDA approved ALK TKI or EGFR TKI,
respectively. Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR
T790M tumor must have received prior osimertinib. Patients with crizotinib-treated ALK
rearranged NSCLC must have received a next generation ALK inhibitor.
Additional Inclusion Criteria:
1. Biopsy proven metastatic melanoma, NSCLC or RCC whose disease has progressed on a
prior regimen containing a PD-1 or PD-L1 inhibitor, without intervening therapy.
2. At least 1 site of disease must be accessible to provide repeat biopsies for tumor
tissue. This site may be a target lesion as long as it will not be made unmeasurable
by the biopsy procedure.
3. Age ≥18, able to understand and sign the informed consent form.
4. ECOG performance status < 2.
5. Any number of previous treatments. Other prior systemic therapies must have been
administered at least 4 weeks before administration of the study drugs; the exception
to this is small molecule inhibitors, which must be stopped at least 2 weeks or after
five half-lives of the drug, whichever is shorter, prior to the start of the study
6. Life expectancy of at least 6 months.
7. A history of previously treated brain metastases is allowed, provided that they are
stable for at least 4 weeks.
8. Willingness to undergo mandatory tumor biopsy prior to initiation of therapy and
before the fifth cycle.
9. Willingness to provide an archival specimen block, if available, for research.
10. Patients must have normal organ and marrow function (as outlined in Section 3.2.2).
11. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 24 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
12. Female subjects of childbearing potential should be willing to use a highly effective
contraception (hormonal or IUD) or be surgically sterile, or abstain from heterosexual
activity for a period of at least 5 months after the last dose of study drug. Subjects
of childbearing potential are those who have not been surgically sterilized or have
not been free from menses for > 1 year.
13. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through at least 7 months after the last dose of study
14. Patients must have at least one measurable lesion at baseline by computed tomography
(CT) or magnetic resonance imaging (MRI) as per RECIST v1.1 criteria.
a. Tumor sites situated in a previously irradiated area, or in an area subjected to
other loco-regional therapy, are not considered measurable unless there has been
demonstrated progression in the lesion. Sites for biopsy must be distinct from target
lesions used for efficacy assessment.
15. Prior focal radiotherapy is allowed. Radiation to brain, pulmonary or intestinal sites
must be completed at least 4 weeks prior to study Day 1. There is no time restriction
prior to study Day 1 for patients who have received radiation to bone, soft tissue or
other sites. No radiopharmaceuticals (strontium, samarium) within 8 weeks before first
dose of study drug administration.
16. Prior surgery that requires general anesthesia must be completed at least 1 week
before first dose of study drug administration. Surgery requiring local/epidural
anesthesia must be completed at least 72 hours before first dose of study drug
administration and patients should have recovered.
1. Untreated brain metastases.
2. A patient who has had prior immune therapy or chemotherapy, within 4 weeks prior to
study Day 1, or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse
events due to a previously administered agent will be excluded. The exception is
targeted therapy that must have been completed at least 2 weeks or after 5 half-lives,
which ever is shorter, prior to study Day 1. Patients who have had prior ipilimumab
must have received their last dose no less than 4 weeks prior to study Day 1.
1. Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
2. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the
inclusion requirements for laboratory parameters.
3. Has had prior treatment with any other CSF1R inhibitor or CD40 agonist
4. Use of corticosteroids to control immune related adverse events at enrollment will not
be allowed, and patients who previously required corticosteroids for symptom control
must be off steroids for at least 2 weeks. Low-dose steroid use (≤10 mg of prednisone
or equivalent) as corticosteroid replacement therapy for primary or secondary adrenal
insufficiency is allowed.
5. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to prior
treatments with the exception of clinically insignificant adverse events such as
alopecia, clinically insignificant laboratory abnormalities, clinically insignificant
rash and Grade 2 neuropathy.
6. History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver toxicity
poorly responsive to steroids with prior anti-PD-1/anti-PDL1 monotherapy.
7. Presence of leptomeningeal disease.
8. Has active autoimmune disease unrelated to use of immune checkpoint inhibitors that
has required systemic treatment in the past year (i.e. with use of disease modifying
agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9. Pregnancy or breast feeding. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with nivolumab, cabiralizumab or
APX005M, breastfeeding must be discontinued if the mother is enrolled on this trial.
10. Patients may not be receiving any other investigational agents and may not have
participated in a study of an investigational agent or using an investigational device
within 4 weeks of the first dose of treatment.
11. Either a concurrent condition (including medical illness, such as active infection
requiring treatment with intravenous antibiotics or the presence of laboratory
abnormalities) or history of a prior condition that places the patient at unacceptable
risk if he/she were treated with the study drug or a medical condition that confounds
the ability to interpret data from the study.
12. Concurrent, active malignancies in addition to those being studied.
13. Active (non-infectious) pneumonitis.
14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C
(HCV) acute or chronic infection.
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
16. History of myocardial infarction or unstable angina within 3 months prior to Cycle 1,
17. Prisoners, or subjects who are under compulsory detention
18. Current or history of clinically significant muscle disorders (e.g., myositis), recent
unresolved muscle injury, or any condition known to elevate serum CK levels
19. History of anti-drug antibodies, severe allergic, anaphylactic, or other
infusion-related reaction to a previous biologic agent
20. Concomitant use of statins while on study. However, a patient using statins for over 3
months prior to study drug administration and in stable status without CK rise may be
permitted to enroll
21. Open wounds and active skin infections
22. Uveal melanoma in the Phase Ib dose expansion trial