Abstract

The oncology clinical trials are evolving in the era of cancer immunotherapy. In Phase I trials, some severe immune-related adverse events occur beyond the first cycle. This is important to determine the recommended Phase II dose if the treatment duration is long. If there is no dose–response/toxicity relationship, it will not be necessary to push to the maximum tolerated dose. In Phase II trials, companion predictive biomarkers are valuable in cancers with intermediate response rates. Randomized (comparison, selection, or discontinuation) Phase II trials are needed in cancer immunotherapy combination. In Phase III trials, milestone analysis and restricted mean survival time could serve as the alternatives to hazard ratio to fit the survival kinetics of cancer immunotherapy.

Introduction

The designs of Phase I–III clinical trials were established in the era of cancer chemotherapy. To fit the unique feature (dose–response/toxicity relationship) of chemotherapy, the primary endpoints of Phase I trial were to find dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and hence recommended Phase II dose. The primary endpoints of Phase II and III trials were objective response rate (RR) and overall survival (OS), respectively. It implied that a high objective RR can translate to improve OS. Since the beginning of targeted therapy era in 2000, the relevance of traditional primary endpoints had been debated. For example, MTD without chronic toxicity taken into consideration may not define the recommended Phase II dose. Patients with stable disease sometimes derived benefit from targeted therapy. Therefore, objective RRs might not be a surrogate of survival. From the beginning of immunotherapy era in 2010, this issue has become even more complicated as immunotherapy is distinct from chemotherapy and targeted therapy. In this article, I discuss the important aspects of designs of Phase I, II, and III trials under the context of cancer immunotherapy.

Phase I Trials

The objective of a Phase I trial is to determine the appropriate dosage of an agent or combination to be taken into further study and to provide initial pharmacologic and pharmacokinetic studies. It is generally assumed, at this stage of testing, that increased dose is associated with an increased chance of clinical efficacy. Therefore, the Phase I trial is designed as a dose-escalation study to determine the MTD, that is, the maximum dose associated with an acceptable level of DLT (usually defined to be Grade 4 or above hematologic toxicity and Grade 3 or above nonhematologic toxicity). The recommended Phase II dose will take MTD, together with pharmacodynamics, pharmacokinetics, and preliminary antitumor activity into consideration.

Dose-limiting toxicity

In cancer immunotherapy, especially anti-CTLA4 (cytotoxic T lymphocyte antigen 4) antibodies and anti-PD-1 (programmed cell death 1) / PD-L1 (programmed cell death 1 ligand 1) antibodies, the major toxicity is immune-related adverse events (irAEs). The major categories of the irAEs are cutaneous (pruritus, rash, vitiligo [in malignant melanoma]), gastrointestinal (diarrhea and colitis), hepatic (transaminitis), endocrine (hypophysitis [in anti-CTLA4 antibodies] and thyroiditis), and pulmonary (pneumonitis [in anti-PD-1/PD-L1 antibodies]).[1,2] There are variations in time to onset of irAEs. For example, rash could occur as early as the first cycle and hypophysitis tends to appear beyond Cycle 1 in patients with ipilimumab (anti-CTLA4 antibody).[1] The one cycle (3–4 weeks) of the traditional DLT-observing period is not adequate to capture all toxicities severe enough to limit the dose.[3] One practical way is to enroll more patients at each dose level and to take DLTs beyond Cycle 1 and intolerable Grade 2 AEs into consideration, similar to the proposal in the era of targeted therapies.[4]

People tend to think that immune checkpoint modulators, because of monoclonal antibody in nature, are relatively safe. There were no DLTs in the Phase I trials of agonistic antibodies against OX40 (CD134, MORX0916[5] and PF04518600[6]); 4-1BB (CD137, BMS663513 [urelumab][7] and PF05082566 [utomilumab][8]); and GITR (CD357, BMS986156[9] and TRX518[10]). We should not forget the tragic lesson we learned from the Phase I trial of TGN1412, an anti-CD28 agonistic antibody.[11,12]

Maximum tolerated dose and recommended Phase II dose

The assumption behind the MTD is that the dose–response (toxicity) relationship exists. The higher dose of ipilimumab, anti-CLTA4 antibody, confers the higher OS and irAE rate in patients with malignant melanoma.[13] However, the dose–response relationship does not exist in anti-PD-1/PD-L1 antibodies.[14–16] To push the dose of cancer immunotherapy to the highest tolerable (or administered) needs to reconsider.

Pharmacokinetics and pharmacodynamics

The main aspects of pharmacodynamics are the tissue, the assay, and the level of target modulation. All of these are closely related to the appropriate sample size for the pharmacodynamic endpoint. In cancer immunotherapy, tumor biopsies repeated before treatment and on treatment are a better tissue source to study pharmacodynamics. We need more preclinical effort to develop the best assay and the right level of target modulation given that the dose–response (toxicity) relationship might not exist in certain cancer immunotherapy. If we do not have other means to determine the recommended Phase II dose, pharmacodynamics will be the primary endpoint rather than just a proof-of-principle study.

Preliminary antitumor activity – Cohort expansion

Because antitumor activities were observed in malignant melanoma and non-small cell lung cancer (and led to the Food and Drug Administration approval of these two indications) in the Phase I trial of pembrolizumab (KEYNOTE-001), people were optimistic that we will see promising preliminary antitumor activities in each and every Phase I trial in the era of cancer immunotherapy.[17] The sample sizes of the cohort expansion still need to be justified with respect to their primary aim (dose seeking based on dose-limiting toxicities, ineffectiveness, or target modulation) and include interim analyses to allow for early stopping.

Phase II Trials

The objective of Phase II trials is to determine if the drug has antitumor activity against the tumor type in question. For this objective, RR is an appropriate endpoint for evaluating the question posed by the trial. However, it is important to recognize that tumor response is not a direct measure of patient benefit.

Objective response rate

The highest RRs (50%–90% except for microsatellite instability–high colorectal cancer) of single-agent anti-PD-1/PD-L1 antibody are in Hodgkin's lymphoma, Merkel cell carcinoma of the skin, squamous cell carcinoma of the skin, and microsatellite instability–high colorectal cancer (40%). A second group of cancers with intermediate RRs (15%–25% except for cutaneous melanoma) are in cutaneous melanoma (40%), nonsmall cell lung cancer, head-and-neck cancer, gastric cancer, urothelial carcinoma, renal cell carcinoma, and hepatocellular carcinoma. In microsatellite-stable colorectal cancer, pancreatic cancer, prostate cancer, and triple-negative breast cancer, the RRs of single-agent anti-PD-1/PD-L1 antibody are lowest (<10%).[18,19] One practical way is to develop biomarkers (e.g., tumor PD-L1, tumor mutational burden, mismatch repair, and T-cell-inflamed gene signature) predictive of higher RR in the intermediate group. This topic is beyond the scope of this review.[20,21]

Phase III Trials

Progression-free survival

Progression-free survival (PFS) curves, although commonly used for conventional treatment modalities, are not an ideal endpoint for cancer immunotherapy clinical trials. First, on initiation of anti-PD-1/PD-L1 therapy and the subsequent promotion of T-cell recruitment/expansion, preexisting tumor lesions may initially increase and new radiological lesions may transiently appear before obtaining a stable disease or partial/complete response. These pseudo-progressions are classified as progressive diseases per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.[22] Therefore, it seems necessary to use dedicated radiological criteria, such as immune RECIST (iRECIST), to assess these atypical tumor responses, and to capture the spectrum of clinical benefits of cancer immunotherapies.[23] Second, PFS curves do not correlate with the OS benefits of cancer immunotherapies that are explained by long-term responses and by possible sensitization of the tumor to the next line of chemotherapy.

Overall survival

For the design of randomized Phase III trials using OS as the primary endpoint, the paradigm has shifted from the conventional approach based on a proportional hazards model to those that account for the unique survival kinetics observed in immuno-oncology trials. The results of the Phase III trial of ipilimumab in metastatic melanoma demonstrated a 4-month delay (overlapping of the survival curves) and long-term OS of approximately 20%.[24] In Phase III trials comparing chemotherapies with anti-PD-1/PD-L1 antibodies, a “crossing of survival curves” can be observed at about 3 months after starting treatment whereby the survival rate is lower in the immunotherapy arm in the early stages of the study.[25–29] One of the explanations of a “crossing of the survival curves” is hyperprogression which means that a subset of patients might present with accelerated progressive disease on treatment with anti-PD-1/PD-L1 antibodies.[30] At least two randomized Phase III trial designs were proposed based on milestone analysis (e.g., 2-year milestone survival)[31] and restricted mean survival time (e.g., the area under the Kaplan–Meier curves within the window of 36–72 months)[32] to simplify the process of sample size determination while keeping OS as the primary endpoint. The new designs are unaffected by the uncertainty of the survival kinetics demonstrated by cancer immunotherapies.

This is even more complicated when we design the Phase III trials of immunotherapy combination, including immunotherapy plus immunotherapy (e.g., nivolumab + ipilimumab in malignant melanoma), immunotherapy plus chemotherapy (e.g., pembrolizumab + platinum-based doublets in nonsmall cell lung cancer), and immunotherapy plus targeted therapy (e.g., avelumab + axitinib in renal cell carcinoma) versus standard therapy. First, single-agent control arm should be available to show synergism, for example, avelumab + axitinib versus avelumab versus sunitinib in renal cell carcinoma. Second, the “long-term” survival benefit needs to be demonstrated. Third, predictive biomarkers of immunotherapy combination might not be the same as those of immunotherapy single agent.

Summary

In the era of cancer immunotherapy, the designs of clinical trials should be adjusted to find the best dose and schedule of the new drugs and to demonstrate the efficacy in the most precise and efficient way [Table 1].

Table 1:

Comparison of clinical trial design among chemotherapy, targeted therapy, and immunotherapy, as well as immunotherapy combination

Comparison of clinical trial design among chemotherapy, targeted therapy, and immunotherapy, as well as immunotherapy combination
Comparison of clinical trial design among chemotherapy, targeted therapy, and immunotherapy, as well as immunotherapy combination

References

References
1.
Weber
JS,
Kähler
KC,
Hauschild
A.
Management of immune-related adverse events and kinetics of response with ipilimumab
.
J Clin Oncol
2012
;
30
:
2691
7
.
2.
Weber
JS,
Hodi
FS,
Wolchok
JD,
et al.
Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma
.
J Clin Oncol
2017
;
35
:
785
92
.
3.
Kanjanapan
Y,
Day
D,
Butler
MO,
et al.
Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials
.
Eur J Cancer
2019
;
107
:
1
7
.
4.
Postel-Vinay
S,
Collette
L,
Paoletti
X,
et al.
Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted Therapies, an European Organisation for Research and Treatment of Cancer-led study
.
Eur J Cancer
2014
;
50
:
2040
9
.
5.
Infante
JR,
Hansen
AR,
Pishvaian
MJ,
et al.
A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors
.
J Clin Oncol
2016
;
34
:
101
.
6.
Hamid
O,
Thompson
JA,
Diab
A,
et al.
First in human (FIH) study of an OX40 agonist monoclonal antibody (mAb) PF-04518600 (PF-8600) in adult patients (pts) with select advanced solid tumors: Preliminary safety and pharmacokinetic (PK)/pharmacodynamic results
.
J Clin Oncol
2016
;
34
:
3079
.
7.
Segal
NH,
Logan
TF,
Hodi
FS,
et al.
Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody
.
Clin Cancer Res
2017
;
23
:
1929
36
.
8.
Segal
NH,
He
AR,
Doi
T,
et al.
Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer
.
Clin Cancer Res
2018
;
24
:
1816
23
.
9.
Siu
LL,
Steeghs
N,
Meniawy
T,
et al.
Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor – related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors
.
J Clin Oncol
2017
;
35
:
104
.
10.
Koon
HB,
Shepard
DR,
Merghoub
T,
et al.
First-in-human phase 1 single-dose study of TRX-518, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody in adults with advanced solid tumors
.
J Clin Oncol
2016
;
34
:
3017
.
11.
Suntharalingam
G,
Perry
MR,
Ward
S,
et al.
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412
.
N Engl J Med
2006
;
355
:
1018
28
.
12.
Kenter
MJ,
Cohen
AF.
Establishing risk of human experimentation with drugs: Lessons from TGN1412
.
Lancet
2006
;
368
:
1387
91
.
13.
Ascierto
PA,
Del Vecchio
M,
Robert
C,
et al.
Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: A randomised, double-blind, multicentre, phase 3 trial
.
Lancet Oncol
2017
;
18
:
611
22
.
14.
Motzer
RJ,
Rini
BI,
McDermott
DF,
et al.
Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial
.
J Clin Oncol
2015
;
33
:
1430
7
.
15.
Robert
C,
Ribas
A,
Wolchok
JD,
et al.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial
.
Lancet
2014
;
384
:
1109
17
.
16.
Herbst
RS,
Baas
P,
Kim
DW,
et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial
.
Lancet
2016
;
387
:
1540
50
.
17.
Kang
SP,
Gergich
K,
Lubiniecki
GM,
et al.
Pembrolizumab KEYNOTE-001: An adaptive study leading to accelerated approval for two indications and a companion diagnostic
.
Ann Oncol
2017
;
28
:
1388
98
.
18.
Ribas
A,
Wolchok
JD.
Cancer immunotherapy using checkpoint blockade
.
Science
2018
;
359
:
1350
5
.
19.
Hirsch
L,
Zitvogel
L,
Eggermont
A,
et al.
PD-loma: A cancer entity with a shared sensitivity to the PD-1/PD-L1 pathway blockade
.
Br J Cancer
2019
;
120
:
3
5
.
20.
Tray
N,
Weber
JS,
Adams
S.
Predictive biomarkers for checkpoint immunotherapy: Current status and challenges for clinical application
.
Cancer Immunol Res
2018
;
6
:
1122
8
.
21.
Fujii
T,
Naing
A,
Rolfo
C,
et al.
Biomarkers of response to immune checkpoint blockade in cancer treatment
.
Crit Rev Oncol Hematol
2018
;
130
:
108
20
.
22.
Hodi
FS,
Hwu
WJ,
Kefford
R,
et al.
Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab
.
J Clin Oncol
2016
;
34
:
1510
7
.
23.
Seymour
L,
Bogaerts
J,
Perrone
A,
et al.
IRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics
.
Lancet Oncol
2017
;
18
:
e143
52
.
24.
Hodi
FS,
O'Day
SJ,
McDermott
DF,
et al.
Improved survival with ipilimumab in patients with metastatic melanoma
.
N Engl J Med
2010
;
363
:
711
23
.
25.
Borghaei
H,
Paz-Ares
L,
Horn
L,
et al.
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
.
N Engl J Med
2015
;
373
:
1627
39
.
26.
Ferris
RL,
Blumenschein
G
Jr.,
Fayette
J,
et al.
Nivolumab for recurrent squamous-cell carcinoma of the head and neck
.
N Engl J Med
2016
;
375
:
1856
67
.
27.
Bellmunt
J,
de Wit
R,
Vaughn
DJ,
et al.
Pembrolizumab as second-line therapy for advanced urothelial carcinoma
.
N Engl J Med
2017
;
376
:
1015
26
.
28.
Powles
T,
Durán
I,
van der Heijden
MS,
et al.
Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial
.
Lancet
2018
;
391
:
748
57
.
29.
Hellmann
MD,
Ciuleanu
TE,
Pluzanski
A,
et al.
Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden
.
N Engl J Med
2018
;
378
:
2093
104
.
30.
Champiat
S,
Ferrara
R,
Massard
C,
et al.
Hyperprogressive disease: Recognizing a novel pattern to improve patient management
.
Nat Rev Clin Oncol
2018
;
15
:
748
62
.
31.
Chen
TT.
Designing late-stage randomized clinical trials with cancer immunotherapy: Can we make it simpler?
Cancer Immunol Res
2018
;
6
:
250
4
.
32.
Pak
K,
Uno
H,
Kim
DH,
et al.
Interpretability of cancer clinical trial results using restricted mean survival time as an alternative to the hazard ratio
.
JAMA Oncol
2017
;
3
:
1692
6
.

Financial support and sponsorship

The author disclosed no funding related to this article.

Conflicts of interest

The author disclosed no conflicts of interest related to this article.

Author notes

For reprints contact:reprints@medknow.com