Rigosertib Plus Pembrolizumab in Treating Patients With Unresectable/Metastatic Melanoma Refractory to PD-1 Inhibitors

Inclusion Criteria:

• Male/female participants who are at least 18 years of age on the day of signinginformed consent with histologically confirmed diagnosis of unresectable ormetastatic cutaneous melanoma will be enrolled in this study.

• Male participants: A male participant must agree to use a contraception duringthe treatment period and for at least 6 days (140 hours) plus an additional 90days (a spermatogenesis cycle) after the last dose of study treatment andrefrain from donating sperm during this period.

• Female participants: A female participant is eligible to participate if she isnot pregnant, not breastfeeding, and at least one of the following conditionsapplies:

• Not a woman of childbearing potential (WOCBP) OR

• A WOCBP who agrees to follow the contractive guidance during the treatmentperiod and for at least 6 days (140 hours) plus 120 days after the lasttreatment dose of study.

• Participants must have progressed on treatment with an anti-PD-1/L1 monoclonalantibody (mAb) administered either as monotherapy or in combination with othercheckpoint inhibitors or other therapies. PD-1 inhibitor treatment progression isdefined by meeting the following criteria:

• For patients treated with anti-PD-1/L1 mAb in the unresectable/metastaticsetting:

• Has received at least 2 doses of an approved anti-PD-1/L1 mAb.

• Has demonstrated disease progression after anti-PD-1/L1 as defined byImmune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST).The initial evidence of progressive disease (PD) is to be confirmed by asecond assessment no less than 4 weeks from the date of the firstdocumented disease progression, in the absence of rapid clinicalprogression.

• Progressive disease has been documented within 12 weeks from the last doseof anti-PD-1/L1 mAb.

• For patients treated with anti-PD-1/L1 mAb in the adjuvant setting:

• Has received at least 2 doses of an approved anti-PD-1/L1 mAb.

• Develops recurrent disease during active adjuvant treatment withanti-PD-1/L1 mAb, OR

• Develops recurrent disease within 6 weeks of last dose of anti-PD-1/L1mAb.

• Progressive disease is determined according to iRECIST (ie, progression byResponse Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 on firstimaging, confirmed with repeat imaging performed at least 4 weeks later). Oncedisease progression is confirmed, the initial date of disease progressiondocumentation will be considered the date of disease progression OR

• The determination of clinical progression is made by the investigator.

• Participants whose disease harbors BRAF V600 mutation must have been exposed toBRAF-targeted therapy, with BRAF-targeted treatment discontinued for eitherprogressive disease or intolerable toxicity.

• The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial.

• Have measurable disease based on iRECIST. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

• Have provided archival tumor tissue sample or newly obtained (within 3 months ofenrollment) core or excisional biopsy of a tumor lesion not previously irradiated.Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.Newly obtained biopsies are preferred to archived tissue.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.Evaluation of ECOG is to be performed within 7 days prior to the first dose of studyintervention.

• White blood cell (WBC) >= 3,000/uL. (Laboratory values must be collected within 10days prior to the start of study intervention [ie, first dose of study treatment]).

• Absolute neutrophil count (ANC) >= 1,500/uL. (Laboratory values must be collectedwithin 10 days prior to the start of study intervention [ie, first dose of studytreatment]).

• Platelets >= 75,000/uL. (Laboratory values must be collected within 10 days prior tothe start of study intervention [ie, first dose of study treatment]).

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L. (Laboratory values must be collected within 10 days prior to the start of study intervention [ie, first dose of studytreatment]).

• Criterion must be met without erythropoietin dependency and without packed redblood cell (pRBC) transfusion within last 2 weeks.

• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculatedcreatinine clearance >= 30 mL/min for subject with creatinine levels > 1.5 xinstitutional ULN (glomerular filtration rate [GFR] can also be used in place ofcreatinine or creatinine clearance [CrCl]). (Laboratory values must be collectedwithin 10 days prior to the start of study intervention [ie, first dose of studytreatment]).

• Serum total bilirubin =< 1.5 X ULN OR =< 3.0 mg/dL for patients with Gilbertsyndrome. (Laboratory values must be collected within 10 days prior to the start ofstudy intervention [ie, first dose of study treatment]).

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN for subjects without liver metastases OR =< 5 X ULN for subjects withliver metastases. (Laboratory values must be collected within 10 days prior to thestart of study intervention [ie, first dose of study treatment]).

• International normalized ration (INR) OR prothrombin time (PT) =< 1.5 x ULN unlessparticipant is receiving anticoagulant therapy as long as PT or activated partialthromboplastin time (aPTT) is within therapeutic range of intended use ofanticoagulants. (Laboratory values must be collected within 10 days prior to thestart of study intervention [ie, first dose of study treatment]).

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant isreceiving anticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants. (Laboratory values must be collected within 10 daysprior to the start of study intervention [ie, first dose of study treatment]).

• Urinalysis negative for hematuria with negative blood and 0 red blood cells (RBCs) (Laboratory values must be collected within 10 days prior to the start of studyintervention [ie, first dose of study treatment]).

Exclusion Criteria:

• Has a diagnosis of primary uveal or mucosal melanoma.

• A WOCBP who has a positive urine pregnancy test within 72 hours of the first dose ofstudy intervention. If the urine test is positive or cannot be confirmed asnegative, a serum pregnancy test will be required. In the event that 72 hours haveelapsed between the screening pregnancy test and the first dose of study treatment,another pregnancy test (urine or serum) must be performed and must be negative inorder for subject to start receiving study medication. Pregnancy testing will beobtained every three months while on study treatment; patients will be withdrawnfrom the study if pregnancy occurs.

• Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks (for immunotherapeutic agents) or within 2 weeks (for targetedtherapeutics) prior to the first dose of study drug. If a subject has experiencedadverse events (AE) from prior treatment, he/she must have recovered from all AEs to < grade 1 or baseline. Patients with < grade 2 neuropathy may be eligible. Patientswith endocrine-related AEs < 2 requiring treatment or physiologic steroidreplacement may be eligible.

• Has received prior radiotherapy within 2 weeks of the first dose of study drug.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (=< 2 weeks of radiotherapy) to non-centralnervous system (CNS) disease.

• If participant has had recent major surgery, the participant must has recoveredadequately from the procedure and/or any complications from the surgery prior to thefirst dose of study drug.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of study drug. Administration of killed vaccines is allowed.

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study drug. Participants who have entered the follow-up phase of aninvestigational study may participate as long as it has been 4 weeks after the lastdose of the previous investigational agent.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

• Has a known additional malignancy that is progressing or has required activetreatment within the past 2 years. Participants with non-melanoma skin cancer (eg,basal cell carcinoma of the skin, squamous cell carcinoma of the skin) or carcinomain situ (eg, breast carcinoma, cervical cancer in situ) that have undergonepotentially curative therapy are not excluded.

• Subjects with untreated active central nervous system (CNS) metastases, active brainmetastases or leptomeningeal metastatic foci. For the subjects with brainmetastases, if they have received treatment and have no evidence of progressivedisease on magnetic resonance imaging (MRI) at least 4 weeks after completion of thetreatment and within 30 days prior to the first dose, they are eligible toparticipate in the study.

• Has a history of severe hypersensitivity (>= grade 3), specifically infusionreaction or anaphylaxis to pembrolizumab and/or any of its excipients.

• Has a history of severe hypersensitivity (>= grade 3 reactions including wheezing,rash, or hypotension) to rigosertib and/or any of its excipients (includingpolyethylene glycol), or anaphylaxis.

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Has an active infection requiring systemic therapy.

• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. Note: no testing for hepatitis B and hepatitisC is required unless mandated by local health authority.

• Has a known history of testing positive for human immunodeficiency virus (HIV) orknown acquired immunodeficiency syndrome (AIDS).

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with theparticipant's participation for the full duration of the study, or is not in thebest interest of the participant to participate, in the opinion of the treatinginvestigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

• Has had an allogenic tissue/solid organ transplant.