A single arm phase II study with 30 patients of leronlimab (PRO 140) in patients with CCR5+ locally advanced or metastatic solid tumors.

Leronlimab (PRO 140) will be administered subcutaneously as weekly dose of 525 mg until disease progression or intolerable toxicity. Subjects participating in this study will be allowed to receive/continue standard-of-care chemotherapy or radiotherapy as per the dosing schedule included on the package insert.

In this study, patients will be evaluated for tumor response approximately every 3 months or according to institution's standard practice by CT, PET/CT or MRI with contrast (per treating investigator's discretion) using the same method as at baseline.

Inclusion Criteria:

1. Must have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumors:

   1. who have disease progression on standard therapy,
   2. who are receiving a standard anticancer treatment but no subsequent approved treatment would be available upon progression,
   3. who are unable to receive standard therapy, or
   4. for whom standard therapy does not exist.

2. Demonstrate CCR5 + by IHC (>10% of primary or metastatic tumor cells shows membranous staining and/or high predominance of CCR5+ tumor-infiltrating leukocytes completed at the reference laboratory of Dr. Hallgeir Rui at Medical College of Wisconsin).

   Note: This test will be done as part of the pre-screening period. It will be performed in archival metastatic tissue. If archival tissue is not available then, fresh biopsy will be done;

3. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion (in case archival tissue is not available);

4. Patients must have measurable disease based on RECIST v1.1;

5. ≥ 18 years of age;

6. Patients must exhibit a/an ECOG performance status of 0-1;

7. Life expectancy of at least 6 months;

8. Patients must have adequate organ and bone marrow function within 28 days prior to registration, as defined below:

   • leukocytes ≥ 3,000/mcL;
   • absolute neutrophil count ≥ 1,500/mcL;
   • platelets ≥ 100,000/mcL;
   • total bilirubin: within normal institutional limits;
   • AST(SGOT) and ALT(SPGT) ≤ 2.5 X institutional upper limit of normal (ULN) (applicable to all patients, irrespective of liver disease or metastasis); and
   • creatinine: within normal institutional limits.

9. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.

10. Females of child-bearing potential (FOCBP) and males must agree to use two medically accepted methods of contraception with hormonal or barrier method of birth control, or abstinence, prior to study entry, for the duration of study participation and for 60 days after the last dose of study drug (Refer to Appendix 1). Should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy; and
    • Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months).

11. FOCBP must have a negative serum pregnancy test at Screening Visit and negative urine pregnancy test prior to receiving the first dose of study drug; and

12. Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days prior to enrollment;
2. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible;
3. Patients who have had prior exposure to CCR5 antagonists are not eligible;
4. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability;
5. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator;
6. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial; and
7. Is pregnant or breastfeeding, or expecting to conceive or have children within the projected duration of the trial, starting with the pre-screening or screening visit through the duration of study participation.

All patients who received at least one dose of leronlimab (PRO 140) were included in the baseline analysis population.

Adverse events (AEs) and serious adverse events (SAEs) were reported from the time of the first treatment and continued up until the final study visit (EOT visit) to evaluate safety of leronlimab (PRO 140) (up to approximately 16 months). All-cause mortality was assessed from first dose through the long-term follow-up period (up to approximately 57 months).

Adverse events were elicited through direct questioning and subject reports. Any abnormalities in visit evaluations, physical examination findings or laboratory results that the investigator believed were clinically significant to the research subject were reported as adverse events.