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Table 1 Summary of ongoing phase I, I/II, and II clinical trials of novel immunotherapy agents

From: Immunotherapies targeting stimulatory pathways and beyond

Category

Target

Drug

Trial

Phase

Type of tumor

Clinical efficacy

Safety

Comments

T cell co-stimulatory targets

CD27

Varlilumab

NCT01460134

I

Advanced solid malignancies

N = 25

ORR 4% and DCR 36% with 1 PR and 8 SD

No DLTs reported

Used as monotherapy

NCT02335918

I/II

Advanced solid malignancies

N = 90

ORR 8% and DCR 37% with 7 PR and 26 SD

5 serious AEs: acute kidney injury, mixed motor neuropathy, pneumonitis, small bowel obstruction, and acute hepatitis

Used with nivolumab

CD70

ARGX-110

NCT01813539

I/II

Advanced, CD70 positive solid or hematologic malignancies

N = 26

DCR 54%, 14 SD with a mean duration of 3.7 months

No DLTs reported

Used as monotherapy

CD40/ CD40L

SEA-CD40

NCT02376699

I

Advanced solid malignancies

N = 34

ORR 3% and DCR 32% with 1 PR and 10 SD

5 cases of DLTs, all infusion-related reactions

Serious AEs included dyspnea (27%), and headache (27%)

Used as monotherapy

CP-870,893

NCT01103635

I

Metastatic melanoma

N = 22

ORR 27%, DCR 59% with 2 CR, 4 PR, and 7 SD

Median PFS was 3.2 months

2 cases DLTs (immune colitis)

Serious AEs: one grade 3 CRS

Used with tremelimumab

JNJ-64457107

(JNJ-107)

NCT02829099

I

Advanced solid malignancies

N = 95

ORR 1%, DCR 25% with 1 PR and 23 SD

2 cases of DLTs: 1 grade 3 headache and 1 grade 3 elevation of transaminases with grade 2 hyperbilirubinemia

Used as monotherapy

APX005M

NCT03123783

I/II

Advanced melanoma and immunotherapy-naïve NSCLC

Phase I:

N = 9

ORR 22%, DCR 67% with 2 PR, 4 SD, 3 PD

Phase II:

N = 10

ORR 20%, DCR 40% with 2 PR, 2 SD, 6 PD

No DLTs reported

Used with nivolumab

NCT02706353

I/II

Metastatic melanoma

–

–

Ongoing

4-1BB/

4-1BBL

Utomilumab (PF05082566)

NCT02179918

I

Advanced solid malignancies

N = 23

ORR 26%, DCR 70% with 2 CR, 4 PR, 10 SD

No DLTs reported

Used with pembrolizumab

ADG106

NCT03802955

I

Advanced solid malignancies or relapsed and refractory NHL

N = 14

ORR 0%, DCR 57% with 8 SD

No DLTs reported

Used as monotherapy

OX40/ OX40L

MEDI0562

NCT02705482

I

Advanced solid malignancies

Durvalumab cohort:

N = 26

ORR 12%, DCR 46% with 3 PR, 9 SD

Tremelimumab cohort:

N = 31

ORR 0%, DCR 29% with 9 SD

5 cases of DLTs (2 with durvalumab and 3 with tremelimumab), no specifics provided

2 grade 5 AEs related to MEDI0562: renal failure (durvalumab cohort) and multiorgan failure (tremelimumab cohort)

Used with durvalumab or tremelimumab

GSK3174998 (GSK998)

NCT02528357

I

Advanced solid malignancies

N = 138

ORR 7%, DCR 14% with 2 CR, 8 PR, 10 SD

2 DLTs in the combination group: 1 grade 3 pleural effusion and 1 grade 1 myocarditis

Used as monotherapy or with pembrolizumab

ATOR-1015

NCT03782467

I

Advanced solid malignancies

No specifics provided. 9/14 patients have discontinued therapy: clinical deterioration (n = 6), death from disease (n = 2), or PD (n = 1)

No DLTs reported

Used as monotherapy

mRNA-2416

NCT03323398

I

Advanced solid or hematologic malignancies

Monotherapy:

N = 39

ORR 0%, DCR of 15% with 6 SD lasting ≥ 14 weeks

No DLTs reported

Used as monotherapy or with durvalumab

GITR/

GITRL

MK-1248

NCT02553499

I

Advanced solid malignancies

Monotherapy:

N = 20

ORR 0% and DCR 15% with 3 SD

Combination:

N = 17

ORR 18% and DCR 47% with 1 CR, 2 PR, 3 SD

No DLTs reported

Used as monotherapy or with pembrolizumab

AMG 228

NCT02437916

I

Advanced solid malignancies

N = 27

ORR 0%, DCR 23% with 7 SD and 20 PD

No DLTs reported

1 grade 5 pneumonitis

Used as monotherapy

BMS-986156

NCT02598960

I/II

Advanced solid malignancies

Monotherapy:

N = 34

ORR 0%, DCR 32% with 11 SD, 18 PD, 5 non-evaluable disease

Combination:

N = 258

ORR 7%, DCR 41% with 2 CR, 19 PR, 84 SD, 117 PD, 18 non-evaluable disease

1 DLT: Grade 4 CK elevation

Used as monotherapy or with nivolumab

Other Direct Immune Stimulatory Targets

LXR

RGX-104

NCT02922764

I

Advanced solid or hematologic malignancies

Monotherapy:

N = 12

DCR 42% with 5 confirmed SD,               1 presumptive PR

Combination:

N = 11

ORR 22%, DCR 66% with 2 CR, 4 SD

Neutropenia was a DLT reported only in the combination cohort

No additional details provided

Used as monotherapy or with docetaxel

IL-2/

IL-2R

RO6874281

NCT02627274

I

Advancedsolid malignancies

No specifics are provided. Long-lasting responses in 3/35 patients

No DLTs reported

Used as monotherapy

hu14.18-IL2

NCT00590824

II

Resectable stage III or IV melanoma

No details are provided on responses for 18 patients (n = 11 neoadjuvant, and n = 7 adjuvant)

6 patients had a median RFS of 5.7 months, a 24-month RFS rate 39% and a 24-month OS of 65%

6 toxicities leading to dose-adjustments: hypotension (n = 3), syncope (n = 1), elevated transaminases (n = 2), and elevated serum creatinine (n = 1)

Used as monotherapy

ALKS 4230

NCT02799095

I/II

Advanced solid malignancies

Monotherapy:

N = 14

ORR 0%, DCR 57% with 8 SD

Combination:

N = 11

ORR 9%, DCR 73% with 1 PR,7 SD

No DLTs reported

Used as monotherapy and with pembrolizumab

Bempegaldesleukin

(NKTR-214 – BEMPEG)

NCT02983045

I/II

Advanced solid malignancies

N = 23

ORR 48%, DCR 70% with 4 CR, 7 PR, 5 SD

No DLTs reported

9% stopped therapy from AEs

Used with nivolumab

Previously untreated stage IV melanoma patients

N = 38

ORR 53% with 13 CR and 7 PR

Median duration of response was not reached

No DLTs reported

10% stopped therapy from AEs

IRX-2

NCT03758781

I

Advanced solid tumors

–

–

Ongoing

IL-15

ALT-803

NCT02523469

I

Stage III or IV NSCLC

N = 21

ORR 29%, DCR 76% with 6 PR, 10 SD

Median PFS: 9.4 months

Median OS: 17.4 months

No DLTs reported

Used with nivolumab

NCT01885897

I/II

Relapsed hematologic malignancies after allogenic bone marrow transplant

N = 33

ORR 6%, DCR 15%, with 1 CR (lasted 7 months), 1 PR (lasted 5 months), 3 SD (lasted ≥ 2 months)

No DLTs reported

Used as monotherapy

n-803

NCT03381586

I

Healthy volunteers

–

No DLTs reported

Used as monotherapy

rhIL-15

NCT03388632

I

Advanced solid malignancies

–

–

Ongoing

A3R

Namodenoson (CF102)

NCT02128958

II

Advanced, refractory HCC and Child–Pugh class B

N = 34

ORR 9% with 3 OR. No specifics about the type of responses are available

OS 4.1 months

No grade 4–5 AEs

Used as monotherapy

CD11b

GB1275

NCT04060342

I/II

Advanced solid malignancies

N = 22

DCR 32% with 7 SD (4 monotherapy and 3 combination cohort)

No DLTs reported

Used as monotherapy or with pembrolizumab or nab-paclitaxel and gemcitabine

STING

MIW815

(ADU-S100)

NCT03172936

I

Advanced solid malignancies and lymphomas

No specifics are provided regarding responses

At time of cut-off, 74% of patients (n = 49) were unenrolled: PD (n = 28), physician decision (n = 18), AEs (n = 2), or death (n = 1)

No DLTs reported

Used in combination with spartalizumab

SB 11,285

NCT04096638

I

Advanced solid malignancies

–

–

Ongoing

TLR-2

Tomaralimab

(OPN-305)

NCT02363491

I/II

Heavily pretreated patients with low and intermediate risk MDS

N = 22

ORR 50%, DCR 73% with 6 CR, 5 PR, 5 SD

No DLTs

No additional toxicity data was provided

Used as monotherapy

TLR-4

G100

NCT02180698

I

Unresectable or metastatic soft tissue sarcomas

N = 14

ORR 14%, DCR 100% with 1 CR, 1 PR, 11 SD

There were no grade 3–5 AEs reported

No additional safety data was provided

Intratumoral monotherapy

TLR-7

NJH395

NCT03696771

I

Non-breast HER2 + advanced malignancies

N = 18

ORR 0%, DCR 50% with no CR or PR, 9 SD

5 DLTs: 3 increased liver enzymes, 1 aseptic meningitis, and 1 meningism

Used as monotherapy

TLR-8

Motolimod

(VTX-2337)

NCT02124850

I

Previously untreated stage II, III, and IV HNSCC

No clinical efficacy reported

No DLTs reported

Used with cetuximab

NCT01836029

II

Recurrent/ metastatic HNSCC

Motolimod:

N = 100

ORR 40%, DCR 62% with 2 CR, 36 PR, 22 SD. Median PFS 6.1 months and median OS 13.5 months

Placebo:

N = 95

ORR 34%, DCR 58% with 5 CR, 27 PR, and 23 SD. PFS 5.9 months, OS 11.3

Serious AEs: vomiting (6%), pneumonia (6%), and dehydration (6%)

Combined with platinum therapy, fluorouracil, and cetuximab

TLR-7 and 8

MEDI9197

NCT02556463

I

Advanced solid malignancies

MEDI9197 monotherapy:

N =35

ORR 0%, DCR 29% with 0 CR, 0 PR, and 10 SD

MEDI9197 with durvalumab:

N = 17

ORR 0%, DCR 18% with 0 CR, 0 PR, 3 SD

Monotherapy: 2 DLTs from CRS

Combination: 1 DLT from hemorrhagic shock from a ruptured liver metastasis

Intratumoral use with or without durvalumab and/or radiation therapy

NKTR-262

NCT03435640

I

Advanced solid malignancies

N = 17

ORR not provided, DCR 41%. Unknown specific number of CR, PR, SD

At least 2 PRs mentioned

1 DLT: transaminitis

Used with bempegaldesleukin

TLR-9

Tilsotolimod

(IMO-2125)

NCT03052205

I

Advanced solid malignancies

N = 51

ORR 0%, DCR 29% with 15 SD

No DLTs reported

Used as intratumoral monotherapy

NCT02644967

I/II

Lefitolimod (MGN1703)

NCT02200081

II

Extensive-stage SCLC

N = 59

ORR 12%, DCR 51%, 0 CR, 7 PR2, SD 23

No grade 5 AEs

5 with grade 4 neutropenia

Maintenance monotherapy

NCT02668770

I

Advanced solid malignancies

–

–

Ongoing

Cavrotolimod

(AST-008)

NCT03684785

I/II

Advanced solid malignancies

–

–

Ongoing

SMAC/ IAP

Birinapant

NCT02587962

I/II

Advanced solid malignancies

N = 18

ORR 11% DCR 22% with 2 PR, 2 SD

1 DLT: grade 3 elevation of transaminases

Used with pembrolizumab

Indirect Immune activators

CXCL12

NOX-A12

NCT03168139

I/II

Metastatic pancreatic and MSS CRC

N = 20

ORR 0%, DCR 25% with 5 SD

Median PFS: 1.87 months

OS: 42% at 6 months and 22% at 12 months

No specifics provided but attributed to pembrolizumab

Used as monotherapy and with pembrolizumab

CXCR4

Balixafortide

NCT01837095

I

Metastatic, HER-2 negative, CXCR4 positive BC

N = 56

ORR 30%, median duration of 3.2 months

Clinical benefit rate 44%, median duration 6.9 months

DCR 76%

There were 16 PR, 25 SD (8 of which lasted > 6 months)

No DLTs reported

Serious AEs in 38%: febrile neutropenia (9%), urinary tract infection (5%), and pneumonia (4%)

Used with eribulin

PI3K

IPI-549

NCT02637531

I

Advanced solid malignancies

N = 30

ORR 7% with 2 PR at 8 weeks

2 DLTs: one grade 3 rash and one grade 3 transaminitis

Used with nivolumab

SAR260301

NCT01673737

I

Advanced solid malignancies

N = 19

ORR 0%, DCR 26% with 5 SD

2 DLTs: one grade 3 pneumonitis and one grade 3 GGT elevation

Used as monotherapy

SYK/ FLT3

TAK-659

NCT02834247

I

Advanced solid malignancies

N = 19

ORR 5%, DCR 63% with 1 PR and 11 PD

3 DLTs: one grade 3 fever, one myocarditis and one left ventricular dysfunction (both thought to be due to nivolumab)

Used with nivolumab

MNK 1/2

Tomivosertib (eFT508)

NCT03616834

II

Advanced solid malignancies

N = 39

ORR 5%, DCR 46% with 3 PR and 15 SD

7 NSCLC patients had DFP of ≥ 24 weeks

7 DLTs: hypersensitivity, hepatic toxicity, and constipation

4 grade 5 AEs but none were attributed to tomivesertib

Used with other ICIs

HDAC

Vorinostat

NCT02619253

I

Advanced, refractory urothelial, renal, and prostate carcinoma

N = 37

ORR 0%, DCR 5% with 2 PR

PFS: 2.8 months (PD-1/PD-L1 naïve urothelial and RCC), 5.2 months (PD-1/PD-L1 resistant patients), and 3.5 months (prostate cancer patients)

No DLTs reported

Used with pembrolizumab

KA2507

NCT03008018

I

Advanced solid malignancies

N = 20

ORR 0%, DCR 35% with 7 SD

No DLTs reported

Used as monotherapy

HSP90

Onalespib

NCT02503709

I

Advanced solid malignancies

N = 21

ORR 5%, DCR 48% with 1 PR that lasted > 10 months, 9 SD

2 DLTs: grade 3 troponin elevation and mucositis

Used with a cyclin-dependent kinase inhibitor (AT7519M)

WEE-1

Adavosertib

NCT02617277

I

Advanced solid malignancies

N = 54

ORR 4%, DCR 36% with 2 PR and 17 SD

3 DLTs: nausea (n = 2) and diarrhea (n = 1)

Used with durvalumab

  1. AE Adverse Event, BC Breast Cancer, CK Creatine Kinase, CR Complete Response, CRC Colorectal Cancer, CRS Cytokine Release Syndrome, DCR Disease Control Rate, DFP Disease-Free Progression, DLT Drug-Limiting Toxicities, GGT Gamma Glutamyl Transferase, HCC Hepatocellular Carcinoma, HNSCC Head and Neck Squamous Cell Carcinoma, IDO Indoleamine 2,3-dioxygenase, MSS Microsatellite Stable, OS Overall Survival, MDS Myelodysplastic Syndrome, NHL Non-Hodgkin’s Lymphoma, NSCLC Non-Small Cell Lung Carcinoma, OR Objective Response, ORR Objective Response Rate, PD Progressive Disease, PFS Progression-Free Survival, PR Partial Response, RCC Renal Cell Carcinoma, RFS Recurrence Free Survival, SCLC Small-Cell Lung Cancer, SD Stable Disease, TLR Toll-Like Receptor, TNBC Triple Negative Breast Cancer