Phase 1b Safety Study of CMB305 in Patients With Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1

• ClinicalTrials.gov Identifier: NCT02387125
• Recruitment Status: Terminated
• First Posted: March 12, 2015
• Last Update Posted: July 1, 2020
• Sponsor: Immune Design
• Information provided by (Responsible Party): Immune Design

Study Description

Brief Summary:

This is a Phase 1b, open label, multi-center study of CMB305 (sequentially administered LV305 [a dendritic cell-targeting viral vector expressing the NY-ESO-1 gene] and G305 [NY-ESO-1 recombinant protein plus GLA-SE]) in patients with melanoma, sarcoma, ovarian cancer, or non-small cell lung cancer that express NY-ESO-1.

Condition or disease	Intervention/treatment	Phase
Sarcoma; Melanoma; Non-small Cell Lung Cancer; Ovarian Cancer	Biological: CMB305; Biological: G100; Drug: Metronomic CPA	Phase 1

Detailed Description:

This study is designed to investigate and examine the safety and immunogenicity of the combinatorial regimen called CMB305, where intradermal LV305 is administered sequentially with intramuscular G305 over three months. During Part 1, a dose escalation design will be utilized in patients with melanoma, NSCLC, ovarian cancer, or sarcoma. After completion of Part 1, the study will be expanded in Part 2 and will enroll patients with NSCLC, ovarian cancer, synovial sarcoma or myxoid/round cell liposarcoma. While this is an exploratory study to evaluate the safety, tolerability and immunogenicity of the CMB305 regimen, the study will also evaluate the safety and response to with oral metronomic CPA or intratumoral G100 in the context of CMB305.

CMB305 is a prime-boost vaccine approach against NY-ESO-1-expressing tumors, designed to generate an integrated, anti-NY-ESO-1 immune response in vivo via a targeted, specific interaction with dendritic cells.

G100 contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist, Glucopyranosyl Lipid A (GLA) that leverages the activation of both innate and adaptive immunity, including dendritic cells, in the tumor microenvironment to create an immune response against the tumor's preexisting diverse set of antigens.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 79 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b Study Evaluating the Safety, Tolerability and Immunogenicity of CMB305 (Sequentially Administered LV305 and G305) in Patients With Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1
• Actual Study Start Date: February 28, 2015
• Actual Primary Completion Date: March 29, 2019
• Actual Study Completion Date: March 29, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 Dose Escalation of CMB305; Patients with melanoma, NSCLC, ovarian cancer, or sarcoma will be enrolled. Patients will receive CMB305, a sequential regimen of LV305 and G305. Two cohorts are planned based on LV305 dose.	Biological: CMB305
Experimental: Part 2 Expansion of CMB305; Arm A will enroll up to 9 patients each with NSCLC or ovarian cancer, or up to 18 patients with the sarcoma subtypes, synovial sarcoma or MRCL. Arm B will enroll up to 9 additional patients with selected sarcoma subtypes to explore subcutaneous (SC) dosing of LV305 and G305 on the same schedule. Arm C will enroll up to 9 patients with synovial sarcoma or MRCL for treatment with CMB305 and with oral metronomic CPA. Arm D will enroll up to 9 patients with synovial sarcoma or MRCL at selected sites for treatment with CMB305 and IT G100. Arm E will enroll up to 6 patients with soft tissue sarcoma any subtype for treatment with a higher dose of CMB305 than previous arms.	Biological: CMB305; Biological: G100; Drug: Metronomic CPA; Other Name: Cytoxan Tablets

Outcome Measures

Primary Outcome Measures :

1. The nature, frequency and severity of adverse events (AEs) and laboratory abnormalities in subjects receiving CMB305 alone or in combination with oral metronomic CPA or G100 [ Time Frame: Up to 5 years since first study injection ]
   To evaluate the safety and tolerability of CMB305 (sequential administered doses of LV305 and G305) alone or in combination with oral metronomic CPA or G100 in subjects with locally advanced, relapsed, or metastatic cancer expressing NY ESO 1

Secondary Outcome Measures :

1. Time to Progression [ Time Frame: Up to 5 years since first study injection ]
   To evaluate clinical responses (by Immune-related Response Criteria (irRC) modified to use RECIST (v 1.1) measurement criteria), time to progression (TTP) and progression-free survival (PFS) as a preliminary assessment of clinical activity
2. Progression Free Survival [ Time Frame: Up to 5 years since first study injection ]
   To evaluate clinical responses (by Immune-related Response Criteria (irRC) modified to use RECIST (v 1.1) measurement criteria), time to progression (TTP) and progression-free survival (PFS) as a preliminary assessment of clinical activity
3. Overall Survival [ Time Frame: Up to 5 years since first study injection ]
   Overall survival (OS), time to progression (TTP), and progression-free survival (PFS) and descriptive tumor responses. Evaluation of response will be by RECIST (v1.1) modified to use irRC measurement criteria and by changes in markers of tumor burden
4. Humoral and cellular immune responses at selected sites, as measured by changes from baseline anti-NY-ESO-1 immunity [ Time Frame: Approximately 14 weeks ]
   To evaluate the cellular and humoral immunogenicity of CMB305 alone or in combination with mCPA or G100 in patients

Other Outcome Measures:

1. To evaluate pre- and post-regimen blood samples for potential biomarkers of immunogenicity and clinical tumor response [ Time Frame: Approximately 14 weeks ]
2. To evaluate available pre- and post-regimen tumor tissue for histologic, immunohistologic, and genomic markers following administration of CMB305 alone or in combination with mCPA or G100 [ Time Frame: Approximately 14 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Locally advanced, relapsed, and/or metastatic cancer
2. Tumor histology consistent with one of the following: In Part 1, Dose Escalation - melanoma, NSCLC, ovarian cancer (including fallopian tube carcinoma), or sarcoma (any subtype). In Part 2, Patient Expansion - NSCLC, ovarian cancer (including fallopian tube carcinoma), or the sarcoma subtypes, synovial sarcoma or myxoid/round cell liposarcoma
3. Tumor specimen positive for NY-ESO-1 expression by IHC and/or RT-PCR. At least one tumor must be accessible and patients must consent for biopsies in Arms C and D.
4. Inadequate response, relapse, and/or unacceptable toxicity with one or more prior systemic, surgical, or radiation cancer therapies, and for whom curative standard therapy is not an option (except patients with NSCLC who must have experienced either an inadequate response, relapse, and/or unacceptable toxicity with two or more prior systemic, surgical, or radiation cancer therapies)

6. ≥ 18 years of age 7. Life expectancy of ≥ 6 months per the investigator 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. ECG without evidence of clinically significant arrhythmia or ischemia 10. If female of childbearing potential (FCBP), willing to undergo pregnancy testing and agrees to use at least one highly effective or two effective contraceptive methods during the dosing period and for three months after last CMB305 injection 11. If male and sexually active with a FCBP, must agree to use highly effective contraception such as latex condom during the dosing period and for three months after last CMB305 injection

Exclusion Criteria:

1. Investigational therapy within 3 weeks prior to CMB305 dosing
2. Prior administration of other NY-ESO-1-targeting immunotherapeutics

3. Significant immunosuppression from:

   1. Concurrent, recent (≤ 4 weeks ago) or anticipated treatment with systemic corticosteroids at any dose, or
   2. Other immunosuppressive medications such as methotrexate, cyclosporine, azathioprine (antihistamines, non-steroidal anti-inflammatory drugs and aspirin permitted) or conditions such as common variable hypogamma-globulinemia or exposures such as large field radiotherapy
4. Cancer therapies, including chemotherapy, radiation, biologics or kinase inhibitors, G-CSF or GM-CSF within 3 weeks prior to the first scheduled CMB305 dosing
5. Psychiatric, other medical illness or other condition that in the opinion of the PI prevents compliance with study procedures or ability to provide valid informed consent
6. Significant autoimmune disease with the exception of alopecia, vitiligo, hypothyroidism or other conditions that have never been clinically active or were transient and have completely resolved and require no ongoing therapy
7. Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failure

8. Inadequate organ function including:

   1. Marrow: Peripheral blood leukocyte count (WBC) < 3000/mm3, absolute neutrophil count ≤ 1500/mm3, platelets < 75000/mm3, or hemoglobin < 10 gm/dL
   2. Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) > 2.5 x ULN, total serum bilirubin > 1.5 x ULN (patients with Gilbert's Disease may be included if their total bilirubin is ≤3.0 mg/dL)
   3. Renal: Creatinine > 1.5x ULN
   4. Other: INR (prothrombin time ratio) or partial thromboplastin time (PTT) >1.5 x ULN
9. History of other cancer within 3 years (except non-melanoma cutaneous malignancies and cervical carcinoma in situ).
10. Active tuberculosis or recent (< 2 week ago) clinically significant infection or evidence of active hepatitis B, hepatitis C or HIV infection
11. For melanoma: Uveal melanoma or LDH >1.1 x ULN

12. Brain metastases considered unstable as:

    1. Without confirmed stability over 60 days in patients previously treated with prior surgery or radiation; OR
    2. Associated with symptoms and/or findings; OR
    3. Requiring corticosteroids or anticonvulsants in the prior 60 days
13. Pregnant, planning to become pregnant, or nursing
14. Known allergy(ies) to any component of CMB305 or CPA

Contacts and Locations

Locations

United States, California

Sarcoma Oncology Center

Santa Monica, California, United States, 90403

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Ohio

University of Cincinnati Cancer Institute

Cincinnati, Ohio, United States, 45267-0502

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98102

Sponsors and Collaborators

Immune Design

More Information

• Responsible Party: Immune Design
• ClinicalTrials.gov Identifier: NCT02387125
• Other Study ID Numbers: V943A-001; IMDZ-C131 ( Other Identifier: ImmuneDesign Protocol Number )
• First Posted: March 12, 2015
• Last Update Posted: July 1, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Additional relevant MeSH terms:

Neoplasm Metastasis; Neoplasms; Neoplastic Processes; Pathologic Processes