Pilot Study of Paclitaxel Plus Pembrolizumab in Metastatic HER2-Negative Breast Cancer

This is an open-label randomized pilot research study to determine if the study drug, pembrolizumab, is safe to use in combination with a chemotherapy drug called paclitaxel. This study will have the following two regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus pembrolizumab. A total of 40 evaluable subjects will be enrolled over an enrollment period of 18-24 months. The study is planned to enroll approximately 20 evaluable subjects in each treatment cohort.

• Pembrolizumab (Drug), also known as Keytruda: IV (in the vein) on day 1 of a 21 day cycle
• Paclitaxel (Drug), also known as Taxol: IV (in the vein) on days 1 and 8 of a 21 day cycle

Primary outcomes

• Number of Participants With at Least One Grade 3 or 4 Treatment-related Adverse Event [From enrollment to at least 30 days following cessation of study treatment. The median time on treatment was 5.5 months.]: Grade 3 or 4 study treatment-related adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced at least one grade 3 or 4 study treatment-related adverse events according to the NCI Common Terminology for Adverse Events, version 4.0. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either paclitaxel, pembrolizumab, or both.

Secondary outcomes

• Number of Subjects With an Objective Response (Per RECIST V1.1) [From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)]: Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by >=30% decrease in sum of longest diameter of target lesions with baseline as reference.
• Progression-free Survival (PFS) Per RECIST 1.1 [From treatment start date to date of progression/death, or censored as described; assessed for approximately 2 years.]: PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per RECIST 1.1 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.
• Overall Survival (OS) [From date of treatment start to date of death, or censored as described; assessed for approximately 5 years.]: OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.
• Number of Subjects With Disease Control (Per RECIST V1.1) [From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)]: Disease control was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by >=30% decrease in sum of longest diameter of target lesions with baseline as reference. SD is indicated by neither sufficient shrinkage to qualify for PR nor sufficient growth from nadir (>=20%) to indicate progression.
• Duration of Response (DoR) [From date of response to date of progression/death, or censored as described above; assessed for approximately 2 years.]: Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS. DoR will be determined for each subject using the RECIST 1.1 criteria.

Sex: All, ages: 18 Years to any

Inclusion Criteria

Subjects must meet all of the following criteria:

1. Histologically or cytological confirmed diagnosis of HER2-negative metastatic breast cancer or locally advanced disease not amenable to resection.

   * Available ER and PR status from tumor sample with either hormone receptor positive or negative tumor(s).
   * For subjects with hormone receptor-positive, HER2-negative metastatic breast cancer, they are eligible if they have already received or been intolerant to at least two lines of endocrine therapies (including the adjuvant and/or metastatic setting), or are appropriate candidates for chemotherapy (i.e. large burden of visceral disease).
2. Measurable disease by RECIST 1.1, or evaluable bone disease, i.e., bone lesions that are lytic or mixed (i.e. lytic + sclerotic) in the absence of measurable lesion. Refer to section 11 for the evaluation of measurable disease.
3. Male or female age ≥18 years.
4. ECOG performance status 0, 1 or 2.
5. Must have normal organ and marrow function as defined below:

   * Hematologic - Absolute neutrophil count ≥1,500/mcL

     \- Platelets ≥75,000/mcL

     \- Hemoglobin ≥ 9 g/dL
   * Renal

     * Creatinine ≤ 1.5X ULN or
     * Measured or calculated creatinine clearance (CrCl) ≥ 30 mL/min for subject with creatinine levels > 1.5X ULN \[CrCl should be calculated per institutional standard; GFR can also be used in place of creatinine or CrCl\]
   * Hepatic

     * Total bilirubin ≤1.5X ULN or for subjects with total bilirubin levels >1.5X ULN, direct bilirubin ≤ULN
     * AST(SGOT)/ALT(SGPT) ≤2.5X ULN
   * Coagulation

     * PT and PTT ≤ 1.5X ULN; subjects receiving anticoagulant therapy are eligible if PT or PTT is within therapeutic range of intended use of anticoagulants per investigator discretion.
     * INR ≤ 1.5; Patients receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation per investigator discretion.
6. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to receiving C1D1.
7. Female subjects of childbearing potential must be willing to use an adequate method of birth control as outlined in Section 8.1.10, be surgically sterile, or abstain from heterosexual activity for the course of the study and 120 days after the last dose of study therapy. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Male subjects of reproductive potential should agree to use an adequate method of contraception starting with the first dose of study therapy and 120 days after the last dose of study therapy. Abstinence is acceptable if this is the established and preferred contraception for the subject.
8. Has completed the screening requirement of a core or punch biopsy of a tumor lesion per Section 5 (bone tissue not acceptable). Biopsy of the breast tumor or other regional areas is acceptable (i.e. lymph nodes, skin lesions).

   * Subjects who are unable to meet the screening requirement of a tumor biopsy due to inaccessible tumor, subject safety concern, or bone-only disease may submit an archived tumor specimen from primary tumor or metastatic biopsy collected within 12 months from consent.
   * Subjects who decline tumor biopsy may submit archived tumor specimen as specified above (within 12 months from consent) only after Sponsor-Investigator approval.
9. Ability to understand and the willingness to sign the written informed consent document.

Exclusion Criteria

Subjects must not meet any of the following criteria:

1. Prior chemotherapy within 3 weeks, prior targeted small molecule therapy or radiation therapy within 2 weeks, or prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to Cycle 1 Day 1.
2. Not recovered (i.e., ≤ Grade 1) from adverse events due to agents previously administered.

   o Note: Subjects with ≤ Grade 2 neuropathy or alopecia of any grade are an exception and may qualify for the study.
3. More than three prior lines of chemotherapy for HER2-negative metastatic disease or for locally advanced disease that is not amenable to resection.

   o Note: Non-Chemotherapy regimens do not count as prior lines (ex: hormonals, biologics)
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137) or has participated in Merck MK-3475 trial(s) and received MK-3475 as part of protocol therapy.
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1
6. Has had major surgery within 3 weeks prior to Cycle 1 Day 1.
7. Has received any other investigational agents within 4 weeks of Cycle 1 Day 1 of study therapy.
8. Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis as indicated by clinical symptoms, cerebral edema, and/or progressive growth.

   o Note: Subjects with treated CNS metastases are eligible if they are asymptomatic, have no requirement for steroids, no requirement for anticonvulsants, and stable CNS radiographic study showing no significant vasogenic edema ≥ 4 weeks since completion of radiation and ≥ 2 weeks since discontinuation of steroids.
9. History of known allergic reaction to paclitaxel
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 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. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. Pregnant women are excluded from this study because paclitaxel is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with paclitaxel, breastfeeding should be discontinued if the mother is treated with paclitaxel. These potential risks also apply to pembrolizumab being used in this study.
12. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired immunodeficiency disorder (AIDS). HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with paclitaxel and pembrolizumab. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
13. Has known active infection with hepatitis B or hepatitis C.
14. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).

    o Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
15. Has a known additional malignancy that progressed or required active treatment within the last 5 years.

    o Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
16. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
17. Has an active infection requiring systemic therapy.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. Has received a live vaccine within 30 days of Cycle 1 Day 1 of study therapy. o Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Participant flow

Outcome results

• Number of Participants With at Least One Grade 3 or 4 Treatment-related Adverse Event (Primary), Count of participants, Participants: Arm A (Phased Pembrolizumab Regimen) 5; Arm B (Concurrent Pembrolizumab Regimen) 6
• Number of Subjects With an Objective Response (Per RECIST V1.1) (Secondary), Count of participants, Participants: Arm A (Phased Pembrolizumab Regimen) 4; Arm B (Concurrent Pembrolizumab Regimen) 8
• Progression-free Survival (PFS) Per RECIST 1.1 (Secondary), Median, Months: Arm A (Phased Pembrolizumab Regimen) 4.1 (1.4 to 6.9); Arm B (Concurrent Pembrolizumab Regimen) 3.9 (1.4 to 6.8)
• Overall Survival (OS) (Secondary), Median, Months: Arm A (Phased Pembrolizumab Regimen) 27.6 (9.7 to NA); Arm B (Concurrent Pembrolizumab Regimen) 9.0 (6.8 to 14.0)
• Number of Subjects With Disease Control (Per RECIST V1.1) (Secondary), Count of participants, Participants: Arm A (Phased Pembrolizumab Regimen) 14; Arm B (Concurrent Pembrolizumab Regimen) 12
• Duration of Response (DoR) (Secondary), Median, Months: Arm A (Phased Pembrolizumab Regimen) 7.3 (5.6 to 8.3); Arm B (Concurrent Pembrolizumab Regimen) 4.0 (2.6 to 8.3)

Adverse events

Time frame: Baseline, during treatment, and through 30 days after study treatment is discontinued, an average of 14 months.

Serious adverse events by term

Other adverse events by term

75 more terms not shown.

• Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016 Jul 20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931. Epub 2016 May 2. PMID 27138582
• Results publication: Tan AR, Chai SJ, Robinson MM, Hellner LB, Gavini N, Sulai N, Turner JD, Atlas J, Graham DL, Induru RR, Kadakia KC, Vallabhanei GD, Heeke AL, Foureau DM, Fisher JG. A pilot study of paclitaxel plus pembrolizumab in patients with metastatic HER2-negative breast cancer (PePPy). Cancer Research. 2022; 82(4_Supplement): P2-14-03

• Study Protocol and Statistical Analysis Plan (PDF, 2021-04-13)
• Informed Consent Form (PDF, 2021-06-09)

• Antoinette Tan, MD, Principal investigator, Atrium Health (formerly Carolinas HealthCare System)