Leronlimab (PRO 140) Combined With Carboplatin in Patients With Cytokine Chemokine Receptor 5 Positive (CCR5+) mTNBC

Phase Ib

Phase Ib is a dose escalation phase with 3 dose levels (cohorts) of leronlimab (PRO 140) administered in combination with a fixed dose of carboplatin at AUC 5 (area under the curve). This dose finding portion of study will follow a "3+3" designed to determine the maximum tolerated dose (MTD) of leronlimab (PRO 140) administered as subcutaneous (SC) injection in subjects with histologically confirmed mTNBC that express CCR5.

Phase II

Phase II is a single arm study with 30 patients in order to test the hypothesis that the combination of carboplatin AUC 5 intravenously and MTD of leronlimab (PRO 140) SC will increase Progression Free Survival (PFS) in patients with CCR5 + mTNBC.

• 350 mg leronlimab (Drug), also known as PRO 140: leronlimab is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.
• 525 mg leronlimab (Drug), also known as PRO 140: leronlimab is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.
• 700 mg leronlimab (Drug), also known as PRO 140: leronlimab is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.
• AUC 5 Carboplatin (Drug), also known as Paraplatin: Carboplatin is an anticancer drug chemotherapy drug.
• Maximum Tolerated Dose (MTD) of leronlimab (Drug), also known as PRO 140: The decision on the MTD will be made following the results obtained from Phase I studies

Primary outcomes

• Phase I: Maximum Tolerated Dose (MTD) of Leronlimab (PRO 140) When Combined With Carboplatin AUC5 [From treatment cycle 1 day 1 (C1D1) until MTD reached (each cycle being 3 weeks), up to 26 weeks]: The MTD is defined as 1 dose level (cohort) below the dose in which dose limiting toxicities (DLTs) were observed in >= 33% of the participants.
• Phase II: Progression Free Survival (PFS) Defined as Time in Months From the Date of First Study Treatment to the Date of Disease Progression or Death From Any Cause, Whichever Comes First. [Planned every 6 to 9 weeks after Phase II study start, until progression or death, assessing up to 2 years after completion of treatment]: All patients who received at least one dose of leronlimab (PRO 140) and carboplatin combination was intended to be included in the primary analyses of PFS. The Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria was planned to be used for objective tumor response assessment.

Secondary outcomes

• Phase I: Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (SAE) Collected From the Time of First Treatment Until Study Termination to Evaluate Safety of Leronlimab (PRO 140) and Carboplatin in Subjects With CCR5+ mTNBC. [From Cycle 1, Day 1 (each treatment cycle is 3 weeks) until last dose of study drug, up to 26 weeks]: For Phase I: Adverse events followed National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. This will be the Number of Participants with Any Adverse Events (AE) or Serious Adverse Events (SAE) collected from the time of first treatment until study termination to evaluate safety of leronlimab (PRO 140) and carboplatin in subjects with CCR5+ metastatic triple negative breast cancer.
• Phase II: Progression Free Survival (PFS) According to RECIST v1.1 in Participants With Detectable Programmed Death-Ligand 1 (PD-L1) [Planned every 6 to 9 weeks after Phase II study start, until progression or death, assessing up to 2 years after completion of treatment]: Phase II: Progression Free Survival (PFS) according to RECIST v1.1 in participants with Detectable Programmed Death-Ligand 1 (PD-L1) Trial was terminated prematurely and no efficacy data was collected from the Phase II portion.
• Phase II: Overall Response Rate (ORR, Defined as Complete Response (CR) + Partial Response (PR)), and Clinical Benefit Rate (CBR, Defined as CR + PR + Stable Disease (SD)) in Subjects With CCR5+ mTNBC Treated With Leronlimab (PRO 140) and Carboplatin. [Planned every 6 to 9 weeks after Phase II study start, until progression or death, assessing up to 2 years after completion of treatment]: Phase II: Overall response rate (ORR, defined as Complete Response (CR) + Partial Response (PR)), and clinical benefit rate (CBR, defined as CR + PR + Stable Disease (SD)) in subjects with CCR5+ mTNBC treated with The trial was terminated early, efficacy data is not available
• Phase II: Time to New Metastases (TTNM) [Planned every 6 to 9 weeks after Phase II study start, until progression or death, assessing up to 2 years after completion of treatment]: Trial was terminated prematurely and no efficacy data was collected.
• Phase II: The Change From Baseline in Circulating Tumor Cells (CTC) Level in the Peripheral Blood. [Planned every 21 days (i.e., Day 1 of each treatment cycle) through treatment completion, an average of 6 months.]: Phase II: The change from baseline in circulating tumor cells (CTC) level in the peripheral blood. No efficacy data was available due to early termination of the trial.
• Phase II: Overall Survival Defined as Time in Months From the Date of First Study Treatment to the Date of Death; [Planned from Day 1 to death from any cause, assessing up to 2 years after completion of treatment.]: Phase II: Overall survival defined as time in months from the date of first study treatment to the date of death; No efficacy data is available due to early termination of the trial.
• Phase II: Number, Frequency, and Severity of AEs Collected From the Time of First Treatment Until 12 Weeks After Study Treatment Completion to Evaluate Safety of Leronlimab (PRO 140) and Carboplatin in Subjects With CCR5+ mTNBC. [Planned from Cycle 1, Day 1 (each treatment cycle is 21 days) to 12 weeks after the last dose of study drug)]: Phase II: Number, frequency, and severity of AEs collected from the time of first treatment until 12 weeks after study treatment completion to evaluate safety of leronlimab (PRO 140) and carboplatin in subjects with CCR5+ mTNBC. No safety data was available from the Phase II portion of the trial due to early termination of the study.

Other outcomes

• Measure Immune Biomarkers (PD-L1) in CTCs, Metastatic Tissue and Immune Cells Such as Cancer Associated Macrophage-like Cells (CAMLs) and Correlate With Therapeutic Benefit (PFS) [Planned every 21 days (i.e., Day 1 of each treatment cycle) through treatment completion, an average of 6 months.]: Measure immune biomarkers (PD-L1) in CTCs, metastatic tissue and immune cells such as CAMLs and correlate with therapeutic benefit (PFS) No subjects were included in this outcome measure due to early termination of the trial.
• Correlation Between CCR5 Expression (CTCs, CAMLs) and PD- L1 Expression. [Planned every 21 days (i.e., Day 1 of each treatment cycle) through treatment completion, an average of 6 months.]: No subjects were included in this outcome measure due to early termination of the trial.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

1. Must have a histologically confirmed diagnosis of TNBC. Must demonstrate HER-2 negative (IHC 0, 1+, or fluorescence in situ hybridization (FISH) negative and ER<1%, and PR < 1%, per ASCO/CAP criteria);
2. Demonstrate CCR5 + by IHC (>10% membranous staining 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 with stage IV de-novo disease or patients that develop recurrence after completion of neoadjuvant or adjuvant therapy are eligible; Note: Patients who have been exposed to carboplatin in neoadjuvant or adjuvant setting will be allowed to enroll, if they have progressed ≥ 6 months from completion of treatment.
5. Phase 1 study section:

   Subjects must have disease recurrence and progression after ≤ 2 line of therapy in metastatic setting but untreated with carboplatin;

   Phase 2 study section:

   Subjects must be naive to chemotherapy or untreated with carboplatin in metastatic setting (first-line) OR excluding carboplatin chemotherapy, subjects must have failed first-line combination of chemotherapy and a checkpoint inhibitor in metastatic setting;
6. Patients must have measurable disease based on RECIST v1.1;
7. Female patients, ≥ 18 years of age;
8. Patients must exhibit a/an ECOG performance status of 0-1;
9. Life expectancy of at least 6 months;
10. 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) \&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.
11. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.
12. 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).
13. 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
14. Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.

Exclusion Criteria:

1. HER-2 overexpressed/amplified metastatic breast cancer (MBC) (Appendix 2 for guidelines from ASCO);
2. ER and or PR expressing tumors;
3. 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;
4. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible;
5. Patients who have had prior exposure to CCR5 antagonists are not eligible;
6. Patients who have a known additional malignancy that is progressing or requires active treatment are not eligible. Patients who have had a prior diagnosis of cancer and if it has been <3 years since their last treatment are not eligible. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer;
7. Has an active infection requiring systemic therapy. Note: Patients must complete any treatment with antibiotics prior to registration;
8. Patients who have a known HIV positive status or known/ active Hepatitis B and/or C infection are not eligible;
9. 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;
10. 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;
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial; and
12. 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.

Participant flow

Outcome results

• Phase I: Maximum Tolerated Dose (MTD) of Leronlimab (PRO 140) When Combined With Carboplatin AUC5 (Primary), Number, mg: Phase 1b: Including 3 Dose Levels (Cohort A, Cohort B, and Cohort C) 700
• Phase II: Progression Free Survival (PFS) Defined as Time in Months From the Date of First Study Treatment to the Date of Disease Progression or Death From Any Cause, Whichever Comes First. (Primary)
• Phase I: Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (SAE) Collected From the Time of First Treatment Until Study Termination to Evaluate Safety of Leronlimab (PRO 140) and Carboplatin in Subjects With CCR5+ mTNBC. (Secondary), Count of participants, Participants: Phase I-Cohort A: 350 mg PRO 140 SC Weekly + AUC 5 Carboplatin 3; Phase I-Cohort B: 525 mg PRO 140 SC Weekly + AUC 5 Carboplatin 4; Phase I-Cohort C: 700 mg PRO 140 SC Weekly + AUC 5 Carboplatin 2
• Phase II: Progression Free Survival (PFS) According to RECIST v1.1 in Participants With Detectable Programmed Death-Ligand 1 (PD-L1) (Secondary)
• Phase II: Overall Response Rate (ORR, Defined as Complete Response (CR) + Partial Response (PR)), and Clinical Benefit Rate (CBR, Defined as CR + PR + Stable Disease (SD)) in Subjects With CCR5+ mTNBC Treated With Leronlimab (PRO 140) and Carboplatin. (Secondary)
• Phase II: Time to New Metastases (TTNM) (Secondary)
• Phase II: The Change From Baseline in Circulating Tumor Cells (CTC) Level in the Peripheral Blood. (Secondary)
• Phase II: Overall Survival Defined as Time in Months From the Date of First Study Treatment to the Date of Death; (Secondary)
• Phase II: Number, Frequency, and Severity of AEs Collected From the Time of First Treatment Until 12 Weeks After Study Treatment Completion to Evaluate Safety of Leronlimab (PRO 140) and Carboplatin in Subjects With CCR5+ mTNBC. (Secondary)
• Measure Immune Biomarkers (PD-L1) in CTCs, Metastatic Tissue and Immune Cells Such as Cancer Associated Macrophage-like Cells (CAMLs) and Correlate With Therapeutic Benefit (PFS) (Other pre specified)
• Correlation Between CCR5 Expression (CTCs, CAMLs) and PD- L1 Expression. (Other pre specified)

Adverse events

Time frame: Adverse events were reported from the time of first treatment until the early termination of the study to evaluate safety of leronlimab (PRO 140) and carboplatin in subjects with CCR5+ mTNBC (up to approximately 30 months).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Trial was terminated prematurely prior to Phase II section of the study.

• Study Protocol (PDF, 2021-01-20)
• Statistical Analysis Plan (PDF, 2021-08-10)

• Jacob Lalezari, MD, Study director, CytoDyn, Inc.