Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC)

Inclusion Criteria

General Inclusion Criteria

• Male/female participants who are at least 18 years of age on the day of signing informed consent with advanced/metastatic cutaneous melanoma, NSCLC or MSS mCRC who meet the following criteria will be enrolled in this study.
• Male participants:

o A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

• Female participants:
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP);OR
• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.

Cohort 1 (MSS mCRC)

• MSS is defined as 0-1 allelic shifts among 3-5 tumor microsatellite loci using a PCR-based assay or immunohistochemistry.
• Must have received prior therapy with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Prior treatment with an anti-PD-1/anti-PD-L1 or anti-CTLA-4 antibody is not allowed.
• Prior treatment with BRAF/MEK inhibitor therapy (if BRAF mutated) and/or EGFR targeted antibody (if KRAS WT) are allowed.
• No more than 2 prior lines of therapy for metastatic disease.
• Adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months; but if not does not count towards prior line of therapy.
• PIV (pan-immune-inflammation) cutoff of 1200 obtained on labs obtained during Screening.

Cohort 2 (PD-1 R/R melanoma)

• PD-1 refractory disease as defined as progression on treatment with anti-PD-(L)1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
• Receipt of at least 2 doses of an approved or investigational anti-PD-(L)1 inhibitor.
• Demonstrated PD after anti-PD-(L)1 inhibitor as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression (as defined by the criteria in the sub-point below).
• Progressive disease that has been documented within 12 weeks from the last dose of anti-PD-(L)1 inhibitor.
• Progressive disease is determined according to iRECIST.
• This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
• Subjects who progressed on/within 3 months of adjuvant therapy with anti-PD-(L)1 inhibitor will be allowed; an adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months.
• Prior treatment with an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody is allowed but not required.
• Prior treatment with BRAF/MEK inhibitor therapy (if BRAF mutated) is allowed but not required.
• No more than 5 prior lines of therapy.

Cohort 3 (PD-1 R/R NSCLC)

• PD-1 refractory disease as defined as progression on treatment with anti-PD-(L)1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
• Has received at least 2 doses of an approved or investigational anti-PD-(L)1 inhibitor.
• Has demonstrated PD after anti-PD-(L)1 inhibitor as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression (as defined by the criteria in the sub-point below).
• Progressive disease has been documented within 12 weeks from the last dose of anti-PD-(L)1 inhibitor.
• Progressive disease is determined according to iRECIST.
• This de