Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC

• ClinicalTrials.gov Identifier: NCT03838367
• Recruitment Status: Active, not recruiting
• First Posted: February 12, 2019
• Last Update Posted: March 21, 2022
• Sponsor: CytoDyn, Inc.
• Collaborator: Amarex Clinical Research
• Information provided by (Responsible Party): CytoDyn, Inc.

Study Description

Brief Summary:

This is a phase Ib/II Study of Leronlimab (PRO 140) combined with Carboplatin in Patients with CCR5+ Metastatic Triple Negative Breast Cancer (mTNBC).

Study population will consist of patients with CCR5-positive, locally advanced or metastatic triple-negative breast cancer (mTNBC) who are naïve to chemotherapy in metastatic setting but have been exposed to anthracyclines and taxane in neoadjuvant and adjuvant settings (first-line).

Condition or disease	Intervention/treatment	Phase
Triple Negative Breast Neoplasms	Drug: 350 mg leronlimab; Drug: 525 mg leronlimab; Drug: 700 mg leronlimab; Drug: AUC 5 Carboplatin; Drug: Maximum Tolerated Dose (MTD) of leronlimab	Phase 1; Phase 2

Detailed Description:

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. 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 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 PFS in patients with CCR5 + mTNBC.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Study of Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ Metastatic Triple Negative Breast Cancer (mTNBC)
• Actual Study Start Date: April 22, 2019
• Estimated Primary Completion Date: July 15, 2022
• Estimated Study Completion Date: September 16, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase I-Cohort A: 350 mg PRO 140 SC weekly + AUC 5 Carboplatin; Cohort A: 350 mg PRO 140 SC weekly + AUC 5 Carboplatin every 3 weeks	Drug: 350 mg leronlimab; leronlimab is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.; Other Name: PRO 140; Drug: AUC 5 Carboplatin; Carboplatin is an anticancer drug chemotherapy drug.
Experimental: Phase I-Cohort B: 525 mg PRO 140 SC weekly + AUC 5 Carboplatin; Cohort B: 525 mg PRO 140 SC weekly + AUC 5 Carboplatin every 3 weeks	Drug: 525 mg leronlimab; leronlimab is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.; Other Name: PRO 140; Drug: AUC 5 Carboplatin; Carboplatin is an anticancer drug chemotherapy drug.
Experimental: Phase I-Cohort C: 700 mg PRO 140 SC weekly + AUC 5 Carboplatin; Cohort C: 700 mg PRO 140 SC weekly + AUC 5 Carboplatin every 3 weeks	Drug: 700 mg leronlimab; leronlimab is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.; Other Name: PRO 140; Drug: AUC 5 Carboplatin; Carboplatin is an anticancer drug chemotherapy drug.
Experimental: Phase II- MTD to be established for the combination treatment; MTD PRO 140 SC + AUC 5 Carboplatin in 30 subjects	Drug: AUC 5 Carboplatin; Carboplatin is an anticancer drug chemotherapy drug.; Drug: Maximum Tolerated Dose (MTD) of leronlimab; The decision on the MTD will be made following the results obtained from Phase I studies; Other Name: PRO 140

Outcome Measures

Primary Outcome Measures :

1. Phase Ib: Maximum Tolerated Dose (MTD) of leronlimab (PRO 140) when combined with carboplatin AUC5 [ Time Frame: Cycle 1 (21 days) ]
2. 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. [ Time Frame: Every 6 to 9 weeks after study start, until progression or death, assessed up to 2 years after completion of treatment ]

Secondary Outcome Measures :

1. Phase I: The number, frequency, and severity of adverse events (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. [ Time Frame: From Cycle 1, Day 1 (each treatment cycle is 21 days) to 12 weeks after the last dose of study drug) ]
2. Phase II: Progression Free Survival (PFS) according to RECIST v1.1 in participants with Detectable Programmed Death-Ligand 1 (PD-L1) [ Time Frame: Every 6 to 9 weeks after study start, until progression or death, assessed up to 2 years after completion of treatment ]
3. 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. [ Time Frame: Every 6 to 9 weeks after study start, until progression or death, assessed up to 2 years after completion of treatment ]
4. Phase II: Time to new metastases (TTNM) [ Time Frame: Every 6 to 9 weeks after study start, until progression or death, assessed up to 2 years after completion of treatment ]
5. Phase II: The change from baseline in circulating tumor cells (CTC) level in the peripheral blood. [ Time Frame: Every 21 days (i.e., Day 1 of each treatment cycle) through treatment completion, an average of 6 months. ]
6. Phase II: Overall survival defined as time in months from the date of first study treatment to the date of death; [ Time Frame: From Day 1 to death from any cause, assessed up to 2 years after completion of treatment. ]
7. Phase II: The 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. [ Time Frame: From Cycle 1, Day 1 (each treatment cycle is 21 days) to 12 weeks after the last dose of study drug) ]

Other Outcome Measures:

1. Measure immune biomarkers (PD-L1) in CTCs, metastatic tissue and immune cells such as CAMLs and correlate with therapeutic benefit (PFS) [ Time Frame: Every 21 days (i.e., Day 1 of each treatment cycle) through treatment completion, an average of 6 months. ]
2. Correlation between CCR5 expression (CTCs, CAMLs) and PD- L1 expression. [ Time Frame: Every 21 days (i.e., Day 1 of each treatment cycle) through treatment completion, an average of 6 months. ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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. Subjects must be untreated or naïve to chemotherapy and/or checkpoint inhibitors exposure in metastatic setting and have been exposed to anthracyclines and taxane in neoadjuvant and adjuvant settings (first-line); 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. Patients must have measurable disease based on RECIST v1.1;
6. Female patients, ≥ 18 years of age;
7. Patients must exhibit a/an ECOG performance status of 0-1;
8. Life expectancy of at least 6 months;

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

11. 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).
12. 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
13. 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 MBC (Appendix 2 for guidelines from ASCO);
2. ER and or PR expressing tumors;
3. Subjects who have had previous systemic chemotherapy for metastatic breast cancer;
4. 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;
5. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible;
6. Patients who have had prior exposure to CCR5 antagonists are not eligible;
7. 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;
8. Has an active infection requiring systemic therapy. Note: Patients must complete any treatment with antibiotics prior to registration;
9. Patients who have a known HIV positive status or known/ active Hepatitis B and/or C infection are not eligible;
10. 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;
11. 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;
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial; and
13. 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.

Contacts and Locations

Locations

United States, California

Quest Clinical Research

San Francisco, California, United States, 94115

United States, Illinois

CD07 Investigational Site

Chicago, Illinois, United States, 60611

Sponsors and Collaborators

CytoDyn, Inc.

Amarex Clinical Research

More Information

• Responsible Party: CytoDyn, Inc.
• ClinicalTrials.gov Identifier: NCT03838367
• Other Study ID Numbers: CD07_TNBC
• First Posted: February 12, 2019
• Last Update Posted: March 21, 2022
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by CytoDyn, Inc.:

TNBC; PRO 140

Additional relevant MeSH terms:

Leronlimab; Breast Neoplasms; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Carboplatin; HIV Antibodies; Antineoplastic Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs