Study of Imprime PGG and Pembrolizumab in Advanced Melanoma and Triple Negative Breast Cancer

NCT02981303 | Completed Phase 2 Results FDA Drug

• 1 other identifier: BT-CL-PGG-MEL/BCA-1621/MK3475
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 10

Brief Summary

Objective: To determine the Overall Response Rate (ORR) to Imprime PGG + pembrolizumab in subjects with advanced melanoma or metastatic TNBC Safety: To characterize the safety of Imprime PGG + pembrolizumab given in combination Hypothesis: Restore (for melanoma) or enhance (for TNBC) sensitivity to checkpoint inhibitors (CPI) by appropriate and effective stimulation of the subject's innate and adaptive immune systems in those subjects who have failed 1st line therapy The study will incorporate Simon's optimal 2-stage design with sample size fixed at 12 subjects each in Stage 1 for advanced melanoma and for Triple Negative Breast Cancer (TNBC) subjects. The safety criterion of ≤ 4 (or ≤ 33%) subjects with Grade 3/4 adverse events in Cycle 1 within either tumor type must be met in order to proceed to Stage 2. The starting dose is 4 mg/kg for Imprime PGG. In the event there are a total of \> 4 (or \> 33%) of subjects with Grade 3/4 adverse events in Cycle 1, the dose of Imprime PGG will be reduced to 2 mg/kg, and Stage 1 will be repeated at a dose of 2 mg/kg with an additional cohort of n=12 subjects. For the dose that meets the safety criterion in Stage 1, at least 1 response in melanoma subjects and 2 responses in TNBC subjects amongst the 12 subjects within each tumor type must be observed in order to proceed to Stage 2. Stage 2 will enroll an additional 17 subjects with melanoma, and 30 subjects with TNBC. For the dose that meets the Stage 1 safety criterion, success will be declared if at least 4 amongst the total of up to 29 subjects with melanoma, and 13 amongst the total of up to 42 subjects with TNBC achieve an objective response.

Conditions

Advanced Melanoma; Triple-Negative Breast Cancer

Outcome Measures

Primary Outcomes (1)

• The Primary Efficacy Endpoint Was ORR, Defined as the Proportion of Subjects Demonstrating CR or PR Based on RECIST v1.1 Criteria.

  The best response was defined as the best response recorded from the start of study treatment until the first PD based on RECIST v1.1 or start of new cancer therapy, whichever occurred earlier. Response assessment occurred every 6 weeks after the first dose of study drug.

  From the start of study treatment until the first PD based on RECIST v1.1 or start of new cancer therapy, whichever occurred earlier, up to 24 months.

Secondary Outcomes (5)

• Time to Response (TTR) Using RECIST v1.1 Criteria

  TTR was defined as time from the date of the first dose to the first response, up to 24 months.

• Complete Response Rate (CRR)

  The time from the date of the first dose to the first response (CR), up to 24 months.

• Duration of Overall Response (DoR) Using RECIST v1.1 Criteria

  time from the first documented evidence of CR or PR (the response prior to the confirmation) until the time of documented PD (based on radiological assessments per RECIST v1.1) or death due to any cause, whichever occurred earlier.

• Progression-Free Survival (PFS) Per RECISTv1.1

  time from the date of the first dose until the first PD or death due to any cause, whichever occurred first.

• Overall Survival (OS)

  Time from date of study day 1 until date of death due to any cause.

Other Outcomes (2)

• Progression Free Survival Based on irRECIST

  time from the date of the first dose until the first PD or death due to any cause, whichever occurred first.

• ORR Based on irRECIST

  the best response recorded from the start of study treatment until PD (PD per RECIST v1.1 or PD confirmed by irRECIST, whichever was later) or start of new anticancer therapy, whichever occurred earlier; up to 24 months.

Study Arms (2)

Melanoma

EXPERIMENTAL

Imprime PGG + Pembrolizumab

Biological: Imprime PGG; Drug: Pembrolizumab

Triple Negative Breast Cancer

EXPERIMENTAL

Imprime PGG + Pembrolizumab

Biological: Imprime PGG; Drug: Pembrolizumab

Interventions

Imprime PGG BIOLOGICAL

Imprime PGG is a soluble, β-1,3/1,6 glucan isolated from the cell wall of a proprietary Saccharomyces cerevisiae yeast strain. Imprime PGG acts as a Pathogen-Associated Molecular Pattern (PAMP). Imprime will be administered at a dose of 4 mg/kg IV over a 2-hour infusion time on Days 1, 8 and 15 of each 3-week treatment cycle.

Also known as: Imprime

Melanoma; Triple Negative Breast Cancer

Pembrolizumab DRUG

Pembrolizumab is a humanized monoclonal antibody against the programmed death receptor-1 protein. Pembrolizumab will be given at a fixed dose of 200 mg IV over 30 minutes on Day 1 of each 3-week treatment cycle after the Imprime infusion.

Also known as: Keytruda

Melanoma; Triple Negative Breast Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have signed an informed document prior to any study-specific procedures or treatment
• Be ≥ 18 years of age at time of consent
• For Melanoma Subjects: Have histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic (Stage IV) melanoma not amenable to local therapy, and irrespective of PD-L1 status
• For TNBC Subjects: Have histologically or cytologically confirmed diagnosis of metastatic (Stage IV) TNBC, and irrespective of PD-L1 status. TNBC is defined as negative immunohistochemistry (IHC) assays for Estrogen Receptor (ER), and Progesterone Receptor (PR), and HER2 negative (IHC 0 or 1+, or 2+ by IHC confirmed negative by FISH)
• Have documented objective radiographic or clinical disease progression after PD-1/PD-L1 +/- anti-CTLA-4 inhibitor therapy (melanoma) or after at least 1 line of chemotherapy for metastatic disease (TNBC)
• Have resolution of all previous treatment-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (less than or equal to Grade 2) or alopecia. If subject received major surgery or radiation therapy of \> 30 Gy, must have recovered from the toxicity and/or complications from the intervention.
• Have at least one radiologically measurable lesion as per RECIST v1.1 defined as a lesion that is at least 10 mm in longest diameter or lymph node that is at least 15 mm in short axis imaged by CT scan or MRI and obtained by imaging within 28 days prior to start of study treatment. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have peripheral blood levels of IgG anti-β-glucan antibody (ABA) of ≥ 20 mcg/mL as determined by an ELISA test within 28 days prior to start of study treatment
• Be willing to consider providing fresh tissue for biomarker analysis, and, based on the adequacy of the tissue sample quality, for assessment of biomarker status. Repeat samples may be required if adequate tissue is not provided. Newly obtained biopsy specimens are preferred to archived samples and formalin-fixed, paraffin-embedded block specimens are preferred to slides.
• Note: Information on 1 tumor biopsy sample is mandatory and is as follows: (1) To determine eligibility, historical (diagnostic) tumor biopsy official pathology report +/- an archival sample. Additional biopsy samples, preferably obtained from the same localized region, are highly desirable when feasible at the following time points: (2) Sample before the first dose of study treatment, (3) Sample after completion of Cycle 2 but before the start of Cycle 3 dosing, and (4) Sample either at the time of response or at the End of Study Visit (if no response).
• Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix 14.3)
• Have life expectancy of 3 months or greater as determined by the treating physician
• Have adequate organ function (all screening labs should be performed within 15 days prior to treatment initiation):
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 x ULN
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases

You may not qualify if:

• Has disease that is suitable for local therapy administered with curative intent
• 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 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
• Has known history of active tuberculosis
• Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
• Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA \[qualitative\] is detected
• Has a history of clinically severe autoimmune disease, or history of organ transplant
• Has a history of ocular melanoma
• Has known hypersensitivity to baker's yeast
• Had previous exposure to Betafectin® or Imprime PGG
• Has hypersensitivity to pembrolizumab or any of its excipients
• Had a prior anti-cancer monoclonal antibody (except immune CPI in the case of melanoma subjects) within 30 days prior to start of study treatment, or failure to recover to CTCAE Grade 1 or better from the adverse events of prior therapies
• Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or who has not recovered from adverse events due to a previously administered agent or major surgery
• Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF, or recombinant erythropoietin) within 4 weeks prior to Study Day 1
• Has known additional malignancy that is progressing or requires active treatment. 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.

Sponsors & Collaborators

• HiberCell, Inc.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (10)

Arizona Center for Cancer Care

Avondale, Arizona, 85392, United States

Location

John Wayne Cancer Institute

Santa Monica, California, 90404, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Sarah Cannon Research Institute

Denver, Colorado, 80218, United States

Location

University Cancer and Blood Center

Athens, Georgia, 30607, United States

Location

Piedmont Cancer Institute

Atlanta, Georgia, 30318, United States

Location

Stony Brook University Cancer Center

Stony Brook, New York, 11794, United States

Location

Thomas Jefferson University Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Millennium Oncology

Houston, Texas, 77090, United States

Location

Related Publications (7)

• Alison Stopeck, Michele Anne Gargano, Nick Niles, Blaine Rathmann, Michael Jon Chisamore, Nandita Bose, and Jose Luis Iglesias. A multicenter, open-label, phase 2 study of odetiglucan (IMPRIME PGG) and pembrolizumab in patients with metastatic breast cancer (mBCA) who have progressed through prior hormonal therapy. Journal of Clinical Oncology. 2022; Volume 40, Number 16_suppl. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS1115

  BACKGROUND

• Chan ASH, Kangas TO, Qiu X, Uhlik MT, Fulton RB, Ottoson NR, Gorden KB, Yokoyama Y, Danielson ME, Jevne TM, Michel KS, Graff JR, Bose N. Imprime PGG Enhances Anti-Tumor Effects of Tumor-Targeting, Anti-Angiogenic, and Immune Checkpoint Inhibitor Antibodies. Front Oncol. 2022 May 26;12:869078. doi: 10.3389/fonc.2022.869078. eCollection 2022.

  PMID: 35692755 BACKGROUND

• Steven O'Day, Virginia F. Borges, Bartosz Chmielowski, Ruta D. Rao, Maysa M. Abu-Khalaf, Alison Stopeck, Petros Nikolinakos, Melinda L. Telli, Bin Xie, Montaser F. Shaheen, Paulette Mattson, Michele Anne Gargano, Joanna Cox, Vassiliki Karantza, Michael Jon Chisamore, Bruno Osterwalder, Nandita Bose, Mark T. Uhlik, and Jeremy Graff. An open label, multicenter phase II study combining imprime PGG (PGG) with pembrolizumab (P) in previously treated metastatic triple-negative breast cancer (mTNBC). Journal of Clinical Oncology. 2019; Volume 37, Number 15_suppl. https://doi.org/10.1200/JCO.2019.37.15_suppl.2550

  RESULT

• Uhlik M, et al. Response and clinical benefit assessment of the combination of the Dectin-1 agonist Imprime PGG and anti-PD-1 Pembrolizumab in chemotherapy-resistant metastatic triple negative breast cancer. San Antonio Breast Cancer Symposium. 2019. PD-02.

  RESULT

• Breast Cancer Plenary Session: O'Day S, et al. A phase 2 trial of pembrolizumab and a novel innate immune activator, Imprime PGG, in metastatic triple negative breast cancer. AACR 2020. (#10531)

  RESULT

• Late Breaking Abstract: Chan ASH, et al. Clinical benefit evident with early immunopharmacodynamic responses in prior-checkpoint failed metastatic melanoma patients treated with Imprime PGG and Pembrolizumab. SITC 2019. (#P862)

  RESULT

• Stopeck AT, Abu-Khalaf M, Borges V, Chmielowski B, Rao R, Xie B, Dudek AZ, Mina L, O'Shaughnessy J, Chisamore M, Mattson P, Gargano M, Cox J, Osterwalder B, Drees J, Harrison B, Chan ASH, Qiu X, Ottoson N, Bose N, Uhlik M, Graff J, Iglesias J. Phase 2 trial of imprime and pembrolizumab immunotherapy in metastatic triple negative breast cancer patients who have progressed beyond first line chemotherapy. J Immunol. 2025 Jul 1;214(7):1529-1538. doi: 10.1093/jimmun/vkaf079.

  PMID: 40338159 DERIVED

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Chief Medical Officer
• Organization: HiberCell

CMO@hibercell.com

651.675.0300

Study Officials

• Jeremy D Graff, PhD

  HiberCell, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2016
• First Posted: December 5, 2016
• Study Start: February 22, 2017
• Primary Completion: December 31, 2020
• Study Completion: December 31, 2020
• Last Updated: July 9, 2024
• Results First Posted: July 9, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (10)