A Phase I/II Study to Assess the Safety and Efficacy of Intratumoral IMO-2125 in Combination with Ipilimumab or Pembrolizumab in Patients with Metastatic Melanoma
The goal of this clinical research study is to find the highest tolerated dose of the study drug IMO-2125 that can be given in combination with either ipilimumab or pembrolizumab to patients with metastatic melanoma. Researchers also want to learn if the study drug combinations can help to control the disease. The safety of the drug combinations will also be studied.
Disease Group: Melanoma
Treatment Agent: IMO-2125,Ipilimumab,Pembrolizumab
Treatment Location: Only at MDACC
Sponsor: Idera Pharmaceuticals
Primary Objective: The primary objective of Phase 1 is to characterize the safety and determine a recommended Phase 2 dose (RP2D) of IMO-2125 when administered in combination with ipilimumab or when administered in combination with pembrolizumab in patients with metastatic melanoma. The maximum tolerated dose (MTD) and RP2D for IMO-2125 may differ between the combination of IMO-2125 and ipilimumab and the combination of IMO-2125 and pembrolizumab. The primary objective of Phase 2 is to assess preliminary clinical activity of IMO-2125 in combination with ipilimumab or in combination with pembrolizumab at the respective RP2D(s) in patients with metastatic melanoma that is not responsive to PD-1 inhibitor therapy, using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Secondary Objective: The secondary objectives of Phase 1 are to determine the plasma pharmacokinetics (PK) of single-dose IMO-2125 and repeat-dose IMO-2125 administered by intratumoral injection in combination with ipilimumab or pembrolizumab. An additional secondary objective Phase 1 is to describe any preliminary antitumor activity. The secondary objectives of Phase 2 are to further assess the safety and tolerability of IMO-2125 in combination with ipilimumab or in combination with pembrolizumab in patients with metastatic melanoma and to assess treatment response using irRECIST and Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, overall survival (OS), OS at 6 and 12 months, progression-free survival (PFS), PFS at 6 and 12 months, durable response rate (DRR), duration of response (DoR), and disease control rate (DCR). Exploratory Objective: The exploratory objectives of Phase 1 and 2 are to assess pre- and post-treatment blood biomarkers, pre- and post-treatment tumor biopsies for immunologic assessment, and explore any potential association between these biomarker measures and antitumor activity. In addition, anti-IMO-2125 anti-ipilimumab and anti-pembrolizumab antibody formation will be assessed.
IRB Review and Approval Date: 12/03/2015
Recruitment Status: Open
Projected Accrual: N/A
1) Patients must have histologically confirmed metastatic melanoma with
measurable, stage III (lymph node or in transit lesions) or stage IVA,
IVB, or IVC disease.
2) Patients must have symptomatic or radiographic progession during or after treatment with a PD-(L)-1 inhibitor administered either as monotherapy or in combination A) The interval between last PD-1 directed treatment and start of study treatment should be at least 21 days. B) Prior BRAF or MEK inhibitor treatment is not required. However, for patients with known BRAF status: i) Those with BRAF wild type may have had a maximum of two previous systemic regimens for the treatment of melanoma ii) Those with a BRAF mutation may have had a maximum of three previous systemic regimens for the treatment of melanoma iii) Prior ipilimumab is permitted C) Previous treatment with either a PD-1 inhibitor (for patients enrolling on the IMO-2125 + pembrolizumab combination) or CTLA-4 inhibitor (for patients enrolling on the IMO-2125 + ipilimumab combination) should not have been accompanied by dose-limiting toxicity (DLT) for which permanent discontinuation is recommended (per USPI).
3) Phase 1 patients must have at least two measurable tumor lesions >/= 1.0 cm that are accessible to biopsy. Phase 2 patients must have at least one measurable lesion (per RECIST v1.1) which may be the same site that is used for the intratumoral injections.
4) Patients must be >/= 18 years of age.
5) Patients must have Eastern Cooperative Oncology Group Performance Status </= 2.
6) Patients must meet the following laboratory criteria: a. Absolute neutrophil count (ANC) >/= 1.5 x 109/L (1500/mm3) b. Platelet count >/= 100 x 10^9/L (-100,000/mm3) c. Hemoglobin >/= 8.0 g/dL (4.96 mmol/L) d. Serum creatinine </= 1.5 x upper limit of normal (ULN) or 24-hour creatinine clearance >/= 60 mL/minute e. Aspartate aminotransferase (AST) </= 2.5 x ULN; alanine aminotransferase (ALT) </= 2.5 x ULN; AST/ALT < 5 x ULN if liver involvement f. Serum bilirubin </= 1.5 x ULN, except in patients with Gilbert’s Syndrome who must have a total bilirubin < 3 mg/dL
7) Women of childbearing potential (WOCBP) and men must agree to use effective contraceptive methods from Screening throughout the study treatment period and until at least 3 month after the last dose of ipilimumab or at least 4 months after the last dose of pembrolizumab. Non-childbearing potential is defined as a woman who meets either of the following criteria: a) postmenopausal state defined as no menses for 12 months without an alternative medical cause, or b) documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy. Effective contraception methods are defined as one of the following: i) True abstinence, defined as refraining from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e. g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawl are not acceptable methods of contraception.
8) (#7 cont'd) ii) Condoms and spermicide iii)Diaphragm and spermicide iv) Oral or implanted hormonal contraceptive (e. g., Implanon) v) An intra-uterine device (IUD)
9) WOCBP must have a negative pregnancy test (serum and urine) prior to the first dose of study treatment.
10) Patients must be willing and able to sign the informed consent and comply with the study protocol.
11) Patients must have an anticipated life expectancy > 3 months.
1) Patients who have received prior therapy with a TLR agonist,
excluding topical agents. Patients who have received experimental
vaccines or other investigational immune therapies should be discussed
with the Medical Monitor to confirm eligibility.
2) Patients who have received systemic treatment with IFN-a within the previous 6 months prior to enrolling into this study.
3) Patients with known hypersensitivity to any oligodeoxynucleotide.
4) Patients with active autoimmune disease requiring disease-modifying therapy.
5) Patients requiring concurrent systemic steroid therapy higher than physiologic dose (7.5 mg/day of prednisone).
6) Patients with any form of active primary or secondary immunodeficiency.
7) Patients with another primary malignancy that has not been in remission for at least 3 years. The following are exempt from the 3 year limit: non-melanoma skin cancer, curatively treated localized prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and thyroid cancer (except anaplastic).
8) Patients with active systemic infections requiring antibiotics or active hepatitis A, B, or C.
9) Patients who are hepatitis B surface antigen positive.
10) Patients with a known diagnosis of human immunodeficiency virus (HIV) infection or who have a positive HIV blood test at Screening.
11) WOCBP who are pregnant or breast feeding.
12) Patients who have had prior anaphylactic or other severe infusion reaction associated with human antibody administration.
13) Patients with known central nervous system, meningeal, or epidural disease. Patients with stable brain metastases following definitive local treatment are eligible if steroid requirement is less than 7.5 mg/day of prednisone (or equivalent).
14) Patients with impaired cardiac function or clinically significant cardiac disease such as: a.) New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, or cardiomyopathy b.) Unstable angina pectoris </= 6 months prior to study participation c.) Acute myocardial infarction </= 6 months prior to study participation d. Other clinically significant heart disease (i.e., Grade >/= 3 hypertension, history of labile hypertension, or poor compliance with an anti-hypertensive regimen)
15) Ocular melanoma.
Information and next steps
Phase I/Phase II
Melanoma Medical Oncology
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