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Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who initially were treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in nine phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDIs of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In the both groups, however, the decreasing relative dose intensity (RDI) over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies. This article is protected by copyright. All rights reserved.

Background Preclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC). Methods In the dose-escalation phase, patients received AA (0.2–1.5 g/kg, 3-h infusion, once daily, days 1–3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed. Results Thirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1–3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3–4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF. Conclusions The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC. Trial registration ClinicalTrial.gov Identifier: NCT02969681. Electronic supplementary material The online version of this article (10.1186/s12885-019-5696-z) contains supplementary material, which is available to authorized users.

Combining agents has the potential to attenuate resistance in metastatic cancer. However, knowledge of appropriate starting doses for novel drug combinations in clinical trials and practice is lacking. Analysis of 372 published studies was used to ascertain safe starting doses for doublets involving a cytotoxic and targeted agent. Phase I–III adult oncology clinical trial publications (January 1, 2010 to December 31, 2013) were identified (PubMed). The dose of drug used in each combination was compared to the single agent recommended dose [FDA‐approved/recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD)]. Dose percentages were calculated as: (safe dose of drug in combination/dose of drug as single agent at FDA/RP2D/MTD) × 100. Additive dose percentages were the sum of the dose percentage for each drug. A total of 24,326 patients (248 drug combinations) were analyzed. In 38% of studies, both drugs could be administered at 100% of their FDA‐approved/RP2D/MTD dose. The lowest safe additive dose percentage was 41% with poly‐ADP ribose polymerase (PARP) or histone deacetylase inhibitors as the targeted agents; 82%, in the absence of these agents; and 97%, with an antibody in the combination. If one drug was administered at 100% of the single agent dose, the lowest safe dose percentage for the second drug was 17% (cytotoxic at 100%) or 36% (targeted at 100%) of the FDA‐approved/RP2D/MTD dose. The current findings can help inform safe starting doses for novel two‐drug combinations (cytotoxic and targeted agents) in the context of clinical trials and practice., What's new? Cytotoxic and targeted cancer drugs act through distinct mechanisms, and when used in combination they can potentially augment therapeutic effectiveness while minimally impacting toxicity. However, whereas algorithms for safe starting doses for new single‐agent therapies are well established, there are few guidelines for combination therapies. Here, analyses of data from published Phase I–III clinical trials shows that about 38% of patients tolerated combinations in which both drugs were administered at full starting doses. In the majority of patients, significant dose reductions were required to guard against toxicity. Intrapatient dose escalation is possible, however, potentially allowing for increased efficacy.

Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014–2016, ASH/ESMO 2014–2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Overall, 84 studies (N = 3,526 patients, 59 combinations) were analyzed. In 50% of studies, all drugs could be administered at full dose; 63%, in the presence of anti-PD-1/PD-L1 and 36% with anti-CTLA-4. The lowest safe starting dose for a doublet combination including a second immunotherapy was 50% of each drug; 60%, for a targeted agent. Most doublet/triplets combining anti-PD-1/PD-L1 with cytotoxics were tolerable at full doses. Response rates (median [interquartile range]) were higher for 3-drug than 2-drug combinations (53% [33–63%] (N = 23 studies) vs. 23% [14–39%]) (N = 60 studies) (p < 0.0001) with similar rates seen for targeted, cytotoxic, biologic, or additional immunotherapy combinations (p = 0.35). In conclusion, anti-PD-1/PD-L1 checkpoint inhibitors can be safely given with a variety of other immunotherapy and targeted agents, albeit at about half dose. Doublet and triplet combinations with cytotoxics could mostly be given at full doses. Anti-CTLA-4 agents compromised dosing more than anti-PD-1/PD-L1 agents. Response rates were significantly higher for 3- versus 2-drug combinations.

Metastatic cancers harbor complex genomic alterations. Thus, monotherapies are often suboptimal. Individualized combinations are needed in order to attenuate resistance. To help inform selection of safe starting doses for novel, two-agent, targeted drug combinations, we identified clinical trials in adult oncology patients who received targeted drug doublets (PubMed, January 1, 2010 through December 31, 2013). The dose percentage was calculated for each drug: (safe dose in combination divided by single agent full dose) X 100. Additive dose percentage represented the sum of the dose percentage for each drug. A total of 144 studies (N = 8568 patients; 95 combinations) were analyzed. In 51% of trials, each of the two drugs could be administered at 100% of their full dose. The lowest safe additive dose percentage was 60% if targets and/or class of drugs overlapped, or in the presence of mTor inhibitors, which sometimes compromised the combination dose. If neither class nor target overlapped and if mTor inhibitors were absent, the lowest safe additive dose percentage was 143%. The current observations contribute to the knowledge base that informs safe starting doses for new combinations of targeted drugs in the context of clinical trials or practice, hence facilitating customized combination therapies.