This study is a Phase 1, open-label, single institution, dose escalation and dose expansion
study to evaluate the efficacy, safety, and tolerability of APX005M in combination with
nivolumab and ipilimumab in patients with advanced melanoma and RCC.
This trial is a phase 1 study to evaluate the safety and tolerability of APX005M in
combination with nivolumab and ipilimumab. The study will enroll patients with advanced solid
tumors (melanoma, RCC) to determine the recommended phase II dosing (RP2D) of APX005M in
combination with ipilimumab 1mg/kg and nivolumab 3 mg/kg (IPI1 NIVO3) every 3 weeks for four
cycles followed by APX005M in combination with nivolumab 360mg every 3 weeks. APX005M will be
administered at a dose of 0.1 mg/kg every 3 weeks in Dose Level 1 (DL1) and escalated to 0.3
mg/kg every 3 weeks in Dose Level 2 (DL2) (Table 1). The IPI1 NIVO3 regimen is approved for
patients with metastatic RCC.
APX005M is a humanized IgG1 agonistic monoclonal antibody that binds CD40. Nivolumab is a
humanized IgG4 monoclonal antibody directed against PD-1. Ipilimumab is a humanized IgG1κ
monoclonal antibody directed against CTLA-4.
- To assess the safety and tolerability of APX005M in combination with nivolumab and
- To determine the recommended RP2D of APX005M in combination with nivolumab and
ipilimumab in patients with unresectable metastatic melanoma or renal cell carcinoma.
• Determine rate and pattern of AEs in patients treated with APX005M in combination with
nivolumab and ipilimumab
- 1. At least 1 site of disease must be accessible to provide repeat biopsies for tumor
tissue. The biopsy may be waived if not feasible upon discussion with the study PIs.
This site may be a target lesion as long as it will not be rendered unmeasurable by
the biopsy procedure.
2. Age ≥18, able to understand and sign the informed consent form 3. ECOG performance
status < 2 4. No prior systemic immune therapy for advanced (unresectable) disease.
Prior targeted therapy is allowed. Adjuvant therapy is allowed provided that at least
6 months have lapsed from the last dose of an immune checkpoint inhibitor. Prior small
molecule inhibitors must be discontinued within 2 weeks before starting study.
5. Life expectancy of at least 6 months 6. A history of previously treated brain
metastases is allowed, provided that they are stable for at least 4 weeks.
7. Willingness to undergo tumor biopsy (if amenable) prior to initiation of therapy
and on trial.
8. Willingness to provide an archival specimen block, if available, for research 9.
Normal organ function . 10. Female subjects 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.
11. 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.
12. 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
13. 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. Tumor
sites situated in a previously irradiated area, or in an area subjected to other
loco-reginal therapy, are not considered measurable unless there has been demonstrated
progression in the lesion.
14. Prior focal radiotherapy is allowed. Radiation to pulmonary or intestinal sites
must be completed at least 1 week prior to study Day 1. Radiation to the brain must be
completed within 4 weeks prior to initiation of treatment. 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.
15. Major surgery must be completed at least 2 weeks prior to the first dose of study
drug administration and patients should have recovered. Wounds must be healed.
- 1. Untreated brain metastases. 2. A patient who has had prior treatment with immune
therapy for advanced disease. Prior immune checkpoint inhibitors as adjuvant therapy
is allowed provided at least 6 months have lapsed from the last dose. Prior targeted
therapy is allowed as long as 2 weeks have passed.
3. 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.
4. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to prior
treatments with the exceptions such as alopecia listed in Table 2.
5. History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver
toxicity poorly responsive to steroids with prior anti-PD-1/anti-PD-L1 therapy in the
6. Presence of leptomeningeal disease. 7. 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.
8. 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, ipilimumab or
APX005M, breastfeeding must be discontinued if the mother is enrolled on this trial.
9. 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.
10. 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.
11. Concurrent, active malignancies in addition to those being studied (other than
cutaneous squamous cell carcinoma or basal cell carcinoma).
12. Active (non-infectious) pneumonitis. 13. Has a known Human Immunodeficiency Virus
(HIV), Hepatitis B (HBV), or Hepatitis C (HCV) acute or chronic infection.
14. Has received a live vaccine within 30 days prior to the first dose of trial
15. History of myocardial infarction or unstable angina within 3 months prior to Cycle
1, Day 1.
16. Prisoners, or subjects who are under compulsory detention 17. Open wounds and
active skin infections