Melanoma Clinical Trials
A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus Nivolumab in Participants with Previously Untreated Unresectable or Metastatic Melanoma
Treatment Agent: Nivolumab, NKTR-214
Synopsis: The purpose of the study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug called NKTR-214 , when combined with nivolumab versus nivolumab given alone in participants with previously untreated melanoma skin cancer that is either unable to be surgically removed or has spread. NKTR-214 and nivolumab in this informed consent may also be referred to as study medication(s) or treatment.
The study has other objectives as well. Blood and tissue samples will be obtained for research purposes. This is to explore how the study drugs behave in your body and the possible association between proteins and genetic markers in your blood or tumor tissue and how well the study drugs work. In the future, this might help to determine which people respond best to these study drugs. For this reason the results of these tests will not be sent to you or your doctor, will not be used in planning your care, and will not become part of your medical record.
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (adults 18 years or older)/Lansky Performance Score ≥ 80% (minors ages 12-17 only)
- Histologically confirmed stage III (unresectable) or stage IV melanoma
- Treatment-naive participants (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) with the exception of prior adjuvant treatment
- Active brain metastases or leptomeningeal metastases
- Uveal melanoma
- Participants with an active, known or suspected autoimmune disease
A Randomized Phase III Trial of Dabrafenib + Trametinib Followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab Followed by Dabrafenib + Trametinib at Progression in Patients with Advanced BRAFV600 Mutant Melanoma
Treatment Agent: Ipilumumab and Nivolumab
Synopsis: This randomized phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as v-raf murine sarcoma viral oncogene homolog B V600 (BRAFV600) and cannot be removed by surgery. Ipilimumab and nivolumab may block tumor growth by targeting certain cells. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
- Women must not be pregnant or breast-feeding
- All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy
- A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- Women of child-bearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 2 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
- Patients must have measurable disease; all sites of disease must be evaluated within 4 weeks prior to randomization
- Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive
- Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified lab; if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test)
- Patients may have had prior systemic therapy in the adjuvant setting; however, patients may not have had any prior treatment for advanced (measurable metastatic) disease or have had prior treatment with a BRAF or MEK inhibitor or a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD1) pathway blocker; patients may not have had any prior ipilimumab or BRAF inhibitors in the adjuvant setting
- Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting >= 4 weeks prior to entering the study and recovered from adverse events due to those agents; patients must have discontinued radiation therapy >= 2 weeks prior to entering the study and recovered from any adverse events associated with treatment; prior surgery must be >= 4 weeks from registration and patients must be fully recovered from post-surgical complications
- Patients must not receive any other investigational agents while on study or within four weeks prior to registration
- Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) that have been stable on head magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4 weeks following treatment and within 4 weeks of randomization are eligible; patients must not have taken any steroids =< 14="" days="" prior="" to="" randomization="" for="" the="" purpose="" of="" managing="" their="" brain="" metastases;="" patients="" with="" whole="" brain="" irradiation="" for="" treatment="" of="" cns="" metastases="" will="" be="" />
- Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for > 3 years prior to the time of registration; patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
- White blood count >= 3,000/uL
- Absolute neutrophil count (ANC) >= 1,500/uL
- Platelet count >= 100,000/uL
- Hemoglobin > 9 g/dL
- Serum creatinine =< 1.5="" x="" upper="" limit="" of="" normal="" (uln)="" or="" serum="" creatinine="" clearance="" (crcl)="" />= 40 ml/min
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3="" x="" uln="" (="" />< 5="" x="" uln="" for="" patients="" with="" documented="" liver="" />
- Alkaline phosphatase =< 2="" x="" uln="" (="" />< 5="" x="" uln="" for="" patients="" with="" known="" liver="" involvement="" and="" />< 7="" x="" uln="" for="" patients="" with="" known="" bone="" />
- Total bilirubin =< 1.5="" x="" uln="" except="" subjects="" with="" normal="" direct="" bilirubin="" or="" those="" with="" known="" gilbert's="" />
- Serum lactate dehydrogenase (LDH) < 10="" x="" uln="" (patients="" with="" ldh="" /> 10 X ULN are felt to have aggressive disease and should be considered for BRAF inhibitor therapy off protocol)
- Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, history of bleeding diathesis or need for concurrent anticoagulation (international normalized ratio [INR] =< 1.5="" and="" partial="" thromboplastin="" time="" [ptt]="" within="" 1.1="" x="" uln),="" or="" psychiatric="" illness/social="" situations="" that="" would="" limit="" compliance="" with="" study="" requirements,="" interfere="" with="" subject's="" safety,="" or="" obtaining="" informed="" consent;="" therapeutic="" level="" dosing="" of="" warfarin="" can="" be="" used="" with="" close="" monitoring="" of="" prothrombin="" time="" (pt)/inr="" by="" the="" site;="" exposure="" may="" be="" decreased="" due="" to="" enzyme="" induction="" when="" treatment,="" thus="" warfarin="" dosing="" may="" need="" to="" be="" adjusted="" based="" upon="" pt/inr;="" consequently,="" when="" discontinuing="" dabrafenib,="" warfarin="" exposure="" may="" be="" increased="" and="" thus="" close="" monitoring="" via="" pt/inr="" and="" warfarin="" dose="" adjustments="" must="" be="" made="" as="" clinically="" appropriate;="" prophylactic="" low="" dose="" warfarin="" may="" be="" given="" to="" maintain="" central="" catheter="" />
- Patients must not have a history of or evidence of cardiovascular risks including any of the following:
- QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480 msec. at baseline
- History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration
- History within the past 24 weeks prior to registration or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
- Left ventricular ejection fraction (LVEF) =< lower="" limit="" of="" normal="" cardiac="" echo="" or="" multi="" gated="" acquisition="" scan="" />
- Intra-cardiac defibrillator
- Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (ECHO) (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
- History or evidence of current clinically significant uncontrolled cardiac arrhythmias; Clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible
- Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
- Individuals who are human immunodeficiency virus (HIV) infected are eligible
- No known or anticipated interaction between the agents being used in the study, (including supporting medications for protocol specified therapy), and any anti-HIV therapy, (including agents used for prophylaxis) being used by the individual
- Patients with evidence of active hepatitis B virus (HBV) or hepatitis C Virus (HCV) infection are not eligible; patients with cleared HBV and HCV infection will be allowed
- Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), should be evaluated for the presence of target organ involvement and potential need for systemic treatment. If no systemic immune suppression is deemed necessary they can be eligible
- The following medications or non-drug therapies are also prohibited while on treatment in this study:
- Other anti-cancer therapies
- Other investigational drugs
- Patients taking any medications or substances that are strong inhibitors or inducers of cytochrome P450 family 3, subfamily A (CYP3A) or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible
- Patients must not have history of retinal vein occlusion (RVO)
- Patients must not have evidence of interstitial lung disease or pneumonitis
- Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib
- Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures
STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE)
- The patient must have met all eligibility criteria (except as detailed below) at the time of crossover
- RECIST defined measurable disease is not required
- Only prior systemic therapy as part of step 1 is allowed
- Malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to ipilimumab + nivolumab treatment
- History of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib therapy
- Patients can be less than 4 weeks from surgery or SRS to CNS metastases
- There is no restriction on serum LDH at crossover
- Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study principal investigator (PI) at time of crossover
- Patients must have melanoma that is metastatic and clearly progressive on prior therapy
- Patients must be at least 2 weeks and within 12 weeks from documented progressive disease (PD) on Step 1 of current study; all sites of disease must be evaluated within 4 weeks prior to registration
- Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy; patients with immune related toxicities from ipilimumab/nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less
- Patients must have discontinued radiation therapy >= 2 weeks prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications
- Patients are ineligible if they have any currently active CNS metastases; patients who have treated brain metastases (with either surgical resection or SRS) that have been stable on head MRI or contrast CT scan for at least 4 weeks following treatment and within 4 weeks prior to Step 2 registration are eligible; patients crossing over to ipilimumab + nivolumab must not have taken any steroids =< 14="" days="" prior="" to="" registration="" for="" the="" purpose="" of="" managing="" their="" brain="" metastases;="" this="" exclusion="" does="" not="" apply="" for="" patients="" crossing="" over="" to="" dabrafenib="" +="" trametinib;="" patients="" with="" whole="" brain="" irradiation="" for="" treatment="" of="" cns="" metastases="" are="" />
- Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast
The Pisces Study: A Multicenter Phase 2, Open-Label Trial of Intratumoral Pil-12 Plus Electroporation in Combination with Intravenous Pembrolizumab in Patients with Stage III/IV Melanoma who are Progressing on Either Pembrolizumab or Nivolumab Treatment
Treatment Agent: Pembrolizumab, ImmunoPulse tavo
Synopsis: The purpose of this study is to find out what effects, good and/or bad, the combination of a type of gene therapy treatment called plasmid electroporation and pembrolizumab has on your cancer.
For the gene therapy treatment, we will inject a human gene into some of your tumor cells and, in order to make sure that the gene stays in the cells, we will send 6 bursts of electricity (“electroporation”) into the cells. The gene that will be injected into your tumor cells is called pIL-12 (plasmid interleukin-12) and is engineered with genetic material (DNA) to force the tumor to make the IL-12 protein. The number of tumors that you will have treated will be determined by your physician. The combination of pIL-12 injection and electroporation is being tested in other studies but has not been approved by the FDA (Food and Drug Administration).
Pembrolizumab binds to specific marker (PD-1) on immune cells and limits the tumor’s ability to exploit a “natural brake” that can suppress immune responses directed against tumor cells. Pembrolizumab has been approved for use in certain types of a cancers, including melanoma.
This study is being paid for by OncoSec Medical Inc., the company that makes the electroporation device, and is the sponsor of this study. Merck, the company that manufactures Pembrolizumab, will provide the study drug at no cost to study participants.
- Pathologically documented unresectable melanoma, AJCC Stage III or IV. Patients must have histological or cytological confirmed diagnosis of unresectable melanoma with progressive locally advanced or metastatic disease.
- Patients must be refractory to anti-PD-1 monoclonal antibodies (mAb) defined as pembrolizumab or nivolumab as either as monotherapy or in combination with other approved checkpoint inhibitors or targeted therapies according to their approved label, defined as (patients must meet all of the following criteria):
- Received at least 4 doses of anti-PD1 mAb for pembrolizumab; minimum dose of 240 mg given every two weeks for nivolumab in monotherapy; minimum dose of 1 mg/kg given Q3W for nivolumab in combination with ipilimumab
- Progressive disease after anti-PD1 mAb will be defined according to RECIST v1.1.
- Documented disease progression within 24 weeks of the last dose of anti-PD1 mAb.
Resolution/improvement of anti-PD1 mAb-related AEs
- No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from anti-PD1 mAb.
- No history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day prednisone or equivalent dose) for >12 weeks or CTCAE Grade 2 pneumonitis regardless of steroid treatment.
- Minimum of 4 weeks (washout period) from the last dose of anti PD1 mAb.
- Prior treatment with an approved BRAF inhibitor if BRAF V600 mutation-positive.
- Age ≥ 18 years of age on day of signing informed consent.
- Has a performance status of 0 or 1 on the ECOG Performance Scale.
Have measurable disease based on RECIST v1.1, with at least one anatomically distinct lesion. Lesion or lesions must meet all the following baseline criteria:
- Accessible for electroporation,
- Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded)
Demonstrate adequate organ function as defined below. All screening laboratories should be performed within 10 days of treatment initiation.
System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1.5 × 109/L Platelets ≥100 × 109/L Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Renal Creatinine* OR ≤1.5 × the upper limit of normal (ULN) OR Measured or calculated creatinine clearance (CrCl) Glomerular filtration rate (GFR) can also be used instead of creatinine or CrCl ≥ 60 mL/min for patient with creatinine levels >1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels > 1.5× ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN OR ≤5 × ULN for patients with liver metastases Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT)
* Creatinine clearance should be calculated per institutional standard.
- Women of childbearing potential must have negative serum or urine pregnancy test within 72 hours prior to receiving the first study drug administration.
- For women of childbearing potential, must be willing to use an adequate method of contraception from 30 days prior to the first study drug administration and 120 days following last day study drug administration
- Male patients of childbearing potential must be surgically sterile, or must agree to use adequate method of contraception during the study and at least 120 days following the last day of study drug administration.
- Able and willing to provide written informed consent and to follow study instructions.
- Patient has disease that is suitable for local therapy administered with curative intent.
- Patient with a diagnosis of uveal melanoma.
- Patient has a known additional malignancy that is progressing or requires active treatment. 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.
- Clinically active cerebral or non-measurable bone-only metastases. Patients with up to 3 (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy or gamma-knife therapy with no evidence of progression, and have not required steroids, for at least two months prior to enrolment.
- Greater than 3 sites of visceral metastases. For patients with less than or equal to 3 visceral metastases and liver lesions must meet RECIST v1.1 criteria for SD for at least 1 month prior to enrolment.
- Patients with electronic pacemakers or defibrillators.
- Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Patients who have known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected); Note: Patients who have been vaccinated against Hepatitis B and who are positive only for the Hepatitis B surface antibody are permitted to participate in the study.
- Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
- Patients who have received a live-virus vaccination within 30 days of the first dose of treatment. Seasonal flu vaccines that do not contain live virus are permitted.
- Patient has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- Patients who have 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 Cycle 1, Day 1 (baseline).
- Patient has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Patient has a history of interstitial lung disease.
- Patient has an active infection requiring systemic therapy.
- Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
- Patient has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
Note: Patients with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study.
Note: If patient underwent major surgery or radiation therapy of >30 Gy, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study combination therapy.
- Participation in another clinical trial within 30 days of screening. Note: Patients participating in an observational study are an exception to this criterion and may qualify for the study with Sponsor approval
- Patients who have had any targeted small molecule therapy or any immunotherapeutic after their confirmed progression on anti-PD-1 therapy.
- Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Patients who are 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.
An Open-Label, Randomized, Controlled Multi-Center Study of The Efficacy of Daromun (L19IL2 + L19TNF) Neoadjuvant Intratumoral Treatment Followed by Surgery Versus Surgery Alone in Clinical Stage IIIB/C Melanoma Patients
Linda Hosler, BA, BSN-RN
Treatment Agent: L19IL2 and L19TNF
Synopsis: Efficacy of Daromun neoadjuvant treatment followed by surgery to improve in a statistically significant manner the recurrence-free survival (RES) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery alone).
- Diagnosis of clinical stage IIIB and IIIC metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable).
- Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
- Males or females, age ≥ 18 years
- ECOG Performance Status/WHO Performance Status ≤ 1
- Life expectancy of > 24 months
- Absolute neutrophil count > 1.5 x 109/L
- Hemoglobin > 9.0 g/dL
- Platelets > 100 x 109/L
- Total bilirubin ≤ 30 μmol/L (or ≤ 2.0 mg/dl)
- ALT and AST ≤ 2.5 x the upper limit of normal (ULN)
- Serum creatinine < 1.5 x ULN and 24 h creatinine clearance > 60 mL/min
- LDH serum level ≤ 1.5 x ULN
- Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination and/or anti-HBc Ab) negative serum HBV-DNA is also required.
- All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
- All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients in Arm 1).
- Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
- Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
- Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
- Uveal melanoma or mucosal melanoma
- Evidence of distant metastases at screening
- Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry
- Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
- History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
- Inadequately controlled cardiac arrhythmias including atrial fibrillation
- Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
- LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
- Uncontrolled hypertension
- Ischemic peripheral vascular disease (Grade IIb-IV)
- Severe diabetic retinopathy
- Active autoimmune disease
- History of organ allograft or stem cell transplantation
- Recovery from major trauma including surgery within 4 weeks prior to enrollment.
- Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
- Breast feeding female
- Anti-tumor therapy (except small surgery) within 4 weeks before enrollment
- Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment
- Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment
- Patient requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
- Any conditions that in the opinion of the investigator could hamper compliance with the study protocol
A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination with Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma
Treatment Agent: PV-10
Synopsis: Researchers want to find out if an investigational drug called PV-10 given in combination with another drug called pembrolizumab (also called Keytruda®) can help people with metastatic melanoma. PV-10 consists of a red dye (stain with the color red) called rose bengal that is dissolved in a sterile salt solution. Previous laboratory studies have shown that PV-10 gets into tumor cells without getting into normal cells and causes tumor cells to die. In earlier studies of people with melanoma, some melanoma tumors that were injected with PV-10 got smaller or went away. PV-10 has been tested in approximately 200 people with melanoma.
- Age 18 years or older, male or female.
- Histologically or cytologically confirmed diagnosis of melanoma.
- Stage IV melanoma for which surgery is not recommended.
- At least 1 cutaneous or subcutaneous Injectable Lesion with longest diameter at least 5 mm.
- A minimum of 1 measurable Target Lesion (i.e., ≥ 10 mm longest diameter).
- Performance Status: ECOG 0-1.
- Clinical Laboratories:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥100 x 109/L.
- Estimated creatinine clearance (CrCl, by Cockroft-Gault formula) or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2.
- Total bilirubin ≤ 3 times the upper limit of normal (ULN).
- Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN).
- Thyroid function abnormality ≤ CTCAE Grade 2.
- Untreated or clinically active melanoma brain metastases.
- Subjects with ≤ 3 brain metastases and each ≤ 1 cm size that were treated with either surgical resection and/or radiation therapy are eligible for study participation provided (a) there is no evidence of progressive CNS disease on brain imaging at least 30 days after definitive treatment and (b) the subject is not taking prednisone at >10 mg or equivalent daily.
- Subjects with > 1 cm or > 3 in number treated brain metastases are eligible for study participation provided (a) there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy and (b) if the subject is not taking prednisone at >10 mg or equivalent daily.
- Prior treatment with PV-10 or any anti-PD-1 antibody.
- Subjects previously treated with any anti-PD-L1 antibody are eligible for study participation.
- Prior cancer therapy or anti-cancer vaccine within 4 weeks of initial study treatment.
- Known sensitivity to any of the products or components to be administered during dosing.
- Concurrent or Intercurrent Illness:
- History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other systemic autoimmune disease.
- Evidence of clinically significant immunosuppression.
- Impaired wound healing or other extremity complications due to severe or uncontrolled diabetes mellitus in subjects whose Injectable Lesions are located in an extremity.
- Severe peripheral vascular disease (i.e., severe claudication [pain occurring after less than 200 meters of walking], rest pain, ischemic ulceration or gangrene) in subjects Significant concurrent or intercurrent illness, psychiatric disorders, or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise the subject’s safety or compliance or interfere with interpretation of study results.
- Uncontrolled thyroid disease or cystic fibrosis.
- Clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological, endocrine, or central nervous system disorders.
- Malignancy other than melanoma within 2 years of enrollment except for: adequately treated (i.e., with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer.
- Female subjects who are pregnant or lactating.
- Female subjects who have positive serum pregnancy test taken within 14 days of initiation of study treatment.
- Female subjects of childbearing potential (defined as having a menstrual cycle within the past 12 months and not having had a surgical procedure to accomplish sterilization) who are not using highly effective contraception (e.g., oral contraceptives, intrauterine devices, double barrier methods such as condoms and diaphragms, abstinence or equivalent measures).
- Male subjects who are unwilling to use acceptable method of effective
A Phase I, Open-Label, Multicenter Study Investigating the Tolerability and Efficacy of UV1 Vaccine in First-Line Malignant Melanoma Patients Planned for Treatment with Pembrolizumab
Treatment Agent: UV1
Synopsis: You are being asked to take part in this study because you have advanced melanoma and you are planned for treatment with pembrolizumab.
This is a clinical study involving an investigational drug, UV1. An investigational drug is a drug which has not yet been approved by the U.S. Food and Drug Administration (FDA).
The purpose of this study is to investigate the safety and tolerability of administering UV1 when given in combination with pembrolizumab, an FDA-approved cancer drug (immunotherapy) for melanoma. This is the first study of this drug combination.
UV1 has previously been tested in humans in clinical studies for prostate and non-small cell lung cancers. UV1 has also been investigated in combination with ipilimumab in a clinical study for melanoma patients.
- Stage IIIB, IIIC or IV melanoma
- Previously untreated and eligible for pembrolizumab treatment (prior treatment with BRAF and MEK inhibitors permitted) 3) Adequate blood, liver and kidney function 4) Consent to undergo tumor biopsies during the study
- Uveal or ocular malignant melanoma
- History of hematologic or primary solid tumor malignancy with the exception of patients in remission for at least 5 years, as judged by the investigator are allowed
- Prior systemic treatment for unresectable or metastatic melanoma. Exception: Prior treatment with BRAF and MEK inhibitors permitted. A washout period of at least 3-half-lives (median terminal half-life) prior to the first dose of trial treatment must have elapsed.
- Prior therapy with an anti-CTLA4, anti-PD-1, anti-PD-L1, anti-PD-L2 agent or oncolytic virus.
- Known hypersensitivity to GM-CSF
- Women who are breastfeeding, pregnant or expect to be pregnant during the study through 6 months after the last dose
- Men who plan to become a father during the study through 4 months after the last dose of study medication
- Known history of, or any evidence of active, non-infectious pneumonitis
- History of cardiac disease