Metastatic Melanoma

RTS-M101B

Title: A Phase 1b’, Open Label, Single Arm, Multicenter Trial to Evaluate the Safety, Tolerance, Response Rate and Immunological Effects of Repeated Intratumoral Injections of Adenoviral Transduced Autologous Dendritic Cells Engineered to Express hIL-12 (INXN-3001) in Response to an Oral Activator Ligand Administered in Intra-Patient Escalating Doses in Patients With Unresectable Stage III C or IV Malignant Melanoma

Sponsor: Intrexon

Description: The objectives of this amended 1b’clinical trial are to assess safety and effectiveness of four treatment cycles of intratumoral injections of INXN-3001 in combination with 14 daily oral doses of Activator Ligand (AL). The AL dose is administered at a low dose level during the first treatment cycle and then will be escalated for each repeat treatment cycle, provided that the preceding treatment cycle was tolerated by the patient.

Inclusion Criteria:
a. Males or females of all races ≥ 18 years of age;
b. Unresectable Stage III C (in transit) or Stage IV melanoma (M1a, M1b, M1c with LDH ≤ 2x ULN), arising from primary cutaneous, mucosal, or subungual melanoma of any tumor thickness;
c. A minimum of 2-3 accessible lesions (longest diameter ≤3 cm) or palpable tumorinvolved lymph nodes (longest diameter ≤5 cm) for intratumoral injections (INXN-3001) and biopsies;
d. ECOG performance status of 0 or 1;
e. Patients without visible brain metastases as assessed by contrast-enhanced MRI scan within 30 days prior to study entry;
f. Adequate baseline hematological and organ function, assessed by laboratory values within 30 days prior to study entry and prior to AL dose escalation as follows: hemoglobin ≥ 10 g/L, granulocytes > 2500/mm3, lymphocytes > 1000/mm3, platelets > 100,000/ mm3, serum creatinine < 1.5 x ULN, AST, ALT, alkaline phosphatase < 2.5 x ULN, LDH ≤ 2 x ULN, serum bilirubin < 1.5 x ULN, absolute neutrophils > 500/ mm3;
g. An expected survival of at least approximately 6 months in the opinion of the investigator (as assessed mainly by performance status);
h. Females must be post-menopausal or surgically sterile or practice effective
contraception; Men who are not surgically sterile and whose partners are not post menopausal or surgically sterile must practice effective contraception;
i. Normal coagulation parameters as measured by PT/PTT;
j. Signed, IRB-approved voluntary informed consent.

Exclusion Criteria:
a. Active, acute viral, bacterial, or fungal infections requiring specific therapy;
b. HIV-infection due to concerns about ability to mount an effective immune response;
c. Active autoimmune disease requiring steroids (>10 mg prednisolone or comparable) or other immunosuppressive therapy;
d. Patients with detectable brain metastases at the time of screening (or within 30 days prior to study entry), as assessed by contrast-enhanced MRI scans;
e. Patients with lesions > 3cm (LD) or palpable, tumor-involved lymph nodes >5 cm(LD);
f. Patients with a hemoglobin of < 10 g/L;
g. Presence of Stage IV visceral metastases or other distant metastases if LDH >2 x ULN;
h. Patients who have previously been treated with INXN-3001 and AL;
i. Recipients of organ allografts;
j. Other concurrent malignant disease, with the exception of other cancers of the skin;
k. Less than 30 days (before the first dose of study medication) have elapsed since the completion of prior chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any first line therapy; l. Clinically significant cerebrovascular disease;
m. History of or concurrent severe cardiac insufficiency (New York Heart Association Class III or IV) or coronary artery disease;
n. Acute medical conditions such as ischemic heart or lung disease that may be considered an unacceptable anesthetic or operative risk;
o. History of or current bleeding or clotting disorders;
p. Concurrent immunosuppressive therapy such as corticosteroids (>10mg prednisolone or comparable) and cyclosporin A;
q. Concurrent investigational treatments, or treatment with any investigational treatment within the past 30 days (prior to the first dose of study medication);
r. Concurrent medications that are metabolized by the CYP450 3A4 pathway (Section 4.7);
s. Females who are lactating or pregnant;
t. Any medical or psychiatric condition which, in the opinion of the investigator, would unacceptably reduce the safety or delivery of the proposed treatment, or would preclude obtaining voluntary informed consent.

Title:  A Randomized Phase 3 Study of Tasisulam Administered as an Intravenous Infusion on Day 1 of a 28-Day Cycle vs. Paclitaxel as Second-Line Treatment in Patients with Metastatic Melanoma

Sponsor:  Lilly
H8K-MC-JZAO
Description:  To compare the overall survival (OS) of patients who have received one prior regimen of dacarbazine or temozolomide-based chemotherapy for metastatic melanoma when treated with either tasisulam or paclitaxel.

Inclusion Criteria: 
* Histologic and/or cytologic diagnosis of malignant melanoma that is metastatic (Stage IV)
* Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.0)
* At least 18 years of age
* Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Scale
* Have progressed after 1 previous systemic treatment containing dacarbazine or temozolomide for metastatic melanoma
* Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, or other investigational therapy for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) before study enrollment and recovered from the acute effects of therapy (except alopecia)

Exclusion Criteria:
* Have received > 2 previous cytotoxic-based treatment regimens for metastatic melanoma.  An immunotherapy or antibody-based regimen [including vaccination-based treatments], or single agent treatment with a targeted agent (e.g. BRAF or c-Kit inhibitor, are not counted as a prior treatment regimen for determining study eligibility unless either was combined with a chemotherapeutic drug)
* Have documented active central nervous system or leptomeningeal metastasis (brain metastasis) at the time of study entry
* Currently receiving warfarin
* Have primary ocular or mucosal melanoma
* Any previous treatment with paclitaxel or a paclitaxel-containing regimen for metastatic melanoma

BMS CA184-045

Title:  A MultiCenter Treatment Protocol for Expanded Access Use of Ipilimumab (BMS-734016) Monotherapy in Subjects with Unresectable Stage III or Stage IV Melanoma

Sponsor:  Bristol-Myers Squibb Company

Description:  Primary objective is to provide treatment with ipilimumab to subjects who have unresectable Stage III or Stage IV melanoma, who have no alternative treatment options and whose physicians believe that it is appropriate to administer ipilimumab at a dose of 10 mg/kg induction/maintenance.

Inclusion Criteria

* Signed Written Informed Consent
* Histologically confirmed Stage III (unresectable) or Stage IV melanoma
* Must have failed at least one systemic therapy for malignant melanoma or be intolerant to at least one prior systemic treatment. Note: Enrollees must not be eligible for a clinical study with ipilimumab
* Subjects with asymptomatic brain metastases are eligible
* Primary ocular and mucosal melanomas are allowed
* Must be at least 28 days since treatment with chemotherapy, biochemotherapy, or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment. Must have recovered from prior surgery or radiation. Systemic corticosteroids should be eliminated or weaned to the minimum dose before starting ipilimumab treatment. Consult with the Medical Monitor for individual subjects
* ECOG PS 0- 2
* Life expectancy ≥ 16 weeks
* Subjects must have the complete set of baseline (screening/baseline) radiographic images, including but not limited to brain, chest, abdomen, pelvis, and bone scans
* Required values for initial laboratory tests:
* WBC: ≥ 2000/uL (≥ 2 x 10*9*/L) ANC: ≥ 1000/uL (≥ 1 x 10*9*/L) Platelets: ≥ 75 x 103/uL (≥ 75 x 10*9*/L) Hemoglobin: ≥ 9 g/dL (≥ 80 g/L; may be transfused) Creatinine: ≤ 2.0 x ULN AST/ALT: ≤ 2.5 x ULN for subjects without liver metastasis ≤ 5 times for liver metastases Bilirubin: ≤ 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must have a total bilirubin of less than 3.0 mg/dL)
* Men and women, at least 16 years of age
* Prior treatment with an anti-CTLA-4 drug is allowed provided therapy was not discontinued to to drug-related toxicity

Exclusion Criteria

* WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 8 weeks after the last dose of investigational product
* WOCBP using a prohibited contraceptive method
* Women who are pregnant or breastfeeding
* Women with a positive pregnancy test on enrollment or before investigational product administration
* Subjects on any other systemic therapy for cancer, including any other experimental treatment
* Prior treatment with an anti CTLA 4 antibody if treatment failure was due to irAEs or discontinuation was due to an AE/SAE
* Any subject enrolled in a registrational study (ie, CA184024) that has a survival endpoint should not be enrolled in CA184-045. Also, if a subject is eligible for a treatment study, he or she is not eligible for this study
* Presence of active autoimmune disease
* Presence of known hepatitis B or hepatitis C (active) infection, regardless of control on antiviral therapy
* Any subject who has a life threatening condition that requires high-dose immunosuppressants
* Subjects with melanoma who have another active, concurrent, malignant disease, with the exception of adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix