APX005M in Combination With Systemic Pembrolizumab in Patients With Metastatic Melanoma

Phase I/II Dose Escalation and Cohort Expansion of Safety and Tolerability Study of Intratumoral CD40 Agonistic Monoclonal Antibody APX005M in Combination With Systemic Pembrolizumab in Patients With Metastatic Melanoma

You are being asked to take part in this study because you have metastatic (cancer that has spread) melanoma.

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of APX005M that can be given with pembrolizumab that can be given to patients with metastatic melanoma.

The goal of Part 2 of this study is to learn if the combination can help to control metastatic melanoma.

The safety of this drug combination will also be studied.

This is an investigational study. APX005M is not FDA approved or commercially available. It is currently being used for research purposes only. Pembrolizumab is FDA approved and commercially available for the treatment of metastatic melanoma. The combination of these drugs to treat metastatic melanoma is investigational.

The study doctor can explain how the study drug is designed to work.

Up to 41 participants will be treated in this study. All will take part at MD Anderson.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 4 groups of 3 participants will be enrolled in Part 1, and up to 20 participants will be enrolled in Part 2.

If you are enrolled in Part 1, the dose of APX005M you receive will depend on when you join this study. The first group of participants will receive the lowest dose level of APX005M. Each new group will receive a higher dose of APX005M than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of APX005M is found.

If you are enrolled in Part 2, you will receive APX005M at the highest dose that was tolerated in Phase 1

All participants will receive the same dose level of pembrolizumab.

Study Drug Administration:

APX005M will be injected directly into 1 tumor every 3 weeks (Weeks 0, 3, 6, and 9) for up to 4 doses.

The injections may be done with or without the help of a ultrasound, CT, and MRI.

If the doctor thinks it is needed, you may need to stay in the hospital overnight or be monitored by a caregiver for 24 hours after you receive APX005M.

You will receive pembrolizumab by vein 1 time every 3 weeks (Weeks 0, 3, 6, 9, and 12). The first dose of pembrolizumab will be given 1-2 days before or after your first dose of APX005M.

You will be given a diary to write down any injection site reactions you may have.

Study Visits:

Within 1 week before your first APX005M injection:

• You will have a physical exam.
• You will have a punch biopsy or image-guided biopsy of a tumor to check the status of the disease. To collect a biopsy, the area of skin is numbed with anesthetic and a small cut is made to remove all or part of the affected tissue. To collect a punch biopsy, the area of skin is numbed with anesthetic and a small cut is made to remove all or part of the affected tissue. To perform an image-guided biopsy, a needle is inserted into the affected area using imaging such as CT or ultrasound to collect cells or tissue from an organ, lymph node, or suspected tumor mass. The doctor will use the imaging to guide the needle into the area.
• Blood (about 4½ tablespoons) will be drawn to test your immune system. If you can become pregnant, blood (about 1 teaspoon) may be drawn for a pregnancy test or urine may be collected to test for pregnancy.
• The tumors may be measured and photographed.

On Day 1 of Cycle 1:

• You will have a physical exam.
• Blood (about 5½ tablespoons) will be drawn for routine tests and test your immune system.
• The tumor may be measured and photographed.

On Day 2 of Cycle 1:

• Your vital signs (blood pressure, heart rate, temperature, and breathing rate) will be measured.
• Blood (about 1 teaspoon) will be drawn for routine tests.
• You will have a biopsy of one of the injected tumor sites within about 24 hours after the 1st injection to check the status of the disease.

On Day 3 of Cycle 1:

• Your vital signs will be measured.
• Blood (about 5 tablespoons) will be drawn for routine tests and to test your immune system.

On Days 8 and 15 of Cycle 1:

• Your vital signs will be measured.
• Blood (about 1½ teaspoons) will be drawn for routine tests.
• Blood (about 4½ tablespoons) may be drawn to test your immune system (Day 8 only).

On Day 1 of Cycle 2:

• You will have a physical exam.
• Blood (about 5½ tablespoons) will be drawn for routine tests and to test your immune system.

On Days 8 and 15 of Cycle 2:

• Your vital signs will be measured.
• Blood (about 1½ teaspoons) will be drawn for routine tests.
• Blood (about 4½ tablespoons) may be drawn to test your immune system (Day 8 only).

On Day 1 of Cycle 3 (± 3 days):

• Your vital signs will be measured.
• You will have a physical exam.
• You will have a biopsy of one of the injected tumors and one of the tumors for which you did not have an injection to check the status of the disease.
• The tumors may be measured and photographed.
• You will have CT, MRI/CT, and/or an ultrasound to check the status of the disease.
• Blood (about 2½ teaspoons) will be drawn for routine tests. If you can become pregnant, a pregnancy test may be performed. Urine may be collected for the pregnancy test.
• Blood (about 4½ tablespoons) will be drawn to test your immune system.

On Day 1 of Cycle 4:

• Your vital signs will be measured
• You will have a physical exam.
• Blood (about 2½ teaspoons) will be drawn for routine tests
• Blood (about 4½ tablespoons) will be drawn to test your immune system.

On Day 1 of Cycles 5-8:

• Your vital signs will be measured.
• You will have a physical exam.
• Blood (about 1½ teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 5 and 8 ONLY (± 3 days):

• Blood (about 1½ teaspoons) will be drawn for routine tests.
• Blood (about 4½ tablespoons) will be drawn to test your immune system.
• You may have a biopsy of one of the injected tumors and one of the tumors for which you did not have an injection to check the status of the disease (Cycle 5 only).
• The tumors may be measured and photographed.
• You will have CT, MRI/CT, and/or an ultrasound to check the status of the disease.

Cycles beyond Cycle 8:

°You will have CT, MRI/CT, and/or an ultrasound to check the status of the disease (every 3 months for up to 2 years).

Length of Treatment:

You will be on study for up to 2 years. You will be taken off study if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

If your doctor thinks it is in your benefit, you may continue to receive pembrolizumab as standard of care after you are off this study. Your doctor will describe this in more detail.

Off-Study Visit:

If you have to go off study early because the disease got worse or you had intolerable side effects:

• Your vital signs will be measured.
• You will have a physical exam.
• Blood (about 1½ teaspoons) will be drawn for routine tests.
• Blood (about 4½ tablespoons) will be drawn to test your immune system.

Follow-Up:

Within 2 weeks after your last study drug dose and every 8-12 weeks after that, you may have scans to check the status of the disease. Your doctor will decide what type of scans you will have.

If you choose to seek care at another hospital, the study staff will call you every 3 months for up to 2 years after your last study drug dose. You will be asked how you are doing. The calls should last about 5 minutes.

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Histologically or cytologically confirmed malignant melanoma from skin, or mucosal melanoma (i.e. ocular melanoma subjects are not eligible)
3. Measurable, unresectable stage III (in transit lesions) or stage IVA, IVB, IVC disease
4. At least two injectable lesions (amenable for direct injection or through the use of image guidance such ultrasound [US], CT or MRI) defined as any injectable cutaneous, subcutaneous, nodal, or visceral melanoma lesion ≥ 10 mm in longest diameter
5. Age ≥ 18 years
6. ECOG performance status 0 or 1
7. Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
8. Platelet count greater than or equal to 100,000/mm^3
9. WBC >3000/mm^3
10. ANC > 1500/mm^3
11. Hemoglobin >9 g/dL
12. Serum ALT and AST <3 the upper limit of normal (ULN); <5 ULN if there is liver involvement secondary to the tumor
13. Serum creatinine < 2.0 mg/dl
14. Seronegative for HIV antibody
15. Patients with a negative pregnancy test (urine or serum) must be documented within 14 days of screening for women of childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months). Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a barrier method of contraception throughout the study and for 4 months after the last dose of APX005M or Pembrolizumab such as: condom, diaphragm, hormonal, IUD, or sponge plus spermicide. Abstinence is an acceptable form of birth control.

Exclusion Criteria:

1. Patients who have previously received pembrolizumab or PD-/L1 blockade therapy. Adjuvant IFN-a, is allowed if last dose was received at least 6 months of starting study treatment.
2. Active autoimmune disease requiring disease-modifying therapy.
3. Concurrent systemic steroid therapy higher than physiologic dose (>7.5 mg/day of prednisone or equivalent).
4. Any form of active primary or secondary immunodeficiency.
5. History of hematologic malignancy.
6. Active coagulopathy.
7. History of New York Heart Association class 3-4 congestive heart failure or history myocardial infarction within 6 months of starting study treatment.
8. History of arterial thrombosis within 3 months of starting study treatment.
9. Patients with known symptomatic brain metastases requiring systematic corticosteroids. Patients with previous diagnosed brain metastases are eligible if they have completed their treatment and have recovered from acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for their metastases for at least 2 weeks and are neurologically stable. Mild neurological deficits are allowed, if they do not interfere with the ability to judge the safety profile of APX005M.
10. Prior malignancy except the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years.
11. Subjects who have received prior immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1), anti-CD40.
12. Subjects that have received experimental vaccines or other immune therapies should be discussed with the Principal Investigator to confirm eligibility.
13. Active known clinically serious infections (> Grade 2 NCI-CTCAE version 4.03).
14. Prior systemic therapy, radiation therapy, or surgery within the 28 days of starting study treatment. Palliative radiotherapy to a limited field or palliative cryoablation is allowed after consultation with the Principal Investigator, at any time during the study participation including screening.
15. Women of child-bearing potential (WOCBP), women who are pregnant, or women who are nursing.
16. Known or underlying medical condition that, in the opinion of the investigator or sponsor, could make the administration of study drug hazardous to the subjects, or could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of APX005M and Pembrolizumab in treated subjects.
17. Has 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 (eg, FluMist®) are live attenuated vaccines and are not allowed.
18. Has received a TB skin test within 14 days before the first dose of study drug.
19. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.